Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof

ABSTRACT

A compound of Formula (IA) or Formula (IB)  
                 
 
     wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are as defined herein, or a tautomer, prodrug, solvate, or salt thereof; pharmaceutical compositions containing such compounds, and methods of modulating the glucocorticoid receptor function and methods of treating disease-states or conditions mediated by the glucocorticoid receptor function or characterized by inflammatory, allergic, or proliferative processes in a patient using these compounds.

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/386,334, filed on Jun. 6, 2002, which application isherein incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to glucocorticoid mimetics orligands, methods of making such compounds, their use in pharmaceuticalcompositions, and their use in modulating the glucocorticoid receptorfunction, treating disease-states or conditions mediated by theglucocorticoid receptor function in a patient in need of such treatment,and other uses.

BACKGROUND OF THE INVENTION

[0003] Glucocorticoids, a class of corticosteroids, are endogenoushormones with profound effects on the immune system and multiple organsystems. They suppress a variety of immune and inflammatory functions byinhibition of inflammatory cytokines such as IL-1, IL-2, IL-6, and TNF,inhibition of arachidonic acid metabolites including prostaglandins andleukotrienes, depletion of T-lymphocytes, and reduction of theexpression of adhesion molecules on endothelial cells (P. J. Barnes,Clin. Sci., 1998, 94, pp. 557-572; P. J. Barnes et al., TrendsPharmacol. Sci., 1993, 14, pp. 436-441). In addition to these effects,glucocorticoids stimulate glucose production in the liver and catabolismof proteins, play a role in electrolyte and water balance, reducecalcium absorption, and inhibit osteoblast function.

[0004] The anti-inflammatory and immune suppressive activities ofendogenous glucocorticoids have stimulated the development of syntheticglucocorticoid derivatives including dexamethasone, prednisone, andprednisolone (L. Parente, Glucocorticoids, N. J. Goulding and R. J.Flowers (eds.), Boston: Birkhauser, 2001, pp. 35-54). These have foundwide use in the treatment of inflammatory, immune, and allergicdisorders including rheumatic diseases such as rheumatoid arthritis,juvenile arthritis, and ankylosing spondylitis, dermatological diseasesincluding psoriasis and pemphigus, allergic disorders including allergicrhinitis, atopic dermatitis, and contact dermatitis, pulmonaryconditions including asthma and chronic obstructive pulmonary disease(COPD), and other immune and inflammatory diseases including Crohndisease, ulcerative colitis, systemic lupus erythematosus, autoimmunechronic active hepatitis, osteoarthritis, tendonitis, and bursitis (J.Toogood, Glucocorticoids, N. J. Goulding and R. J. Flowers (eds.),Boston: Birkhauser, 2001, pp. 161-174). They have also been used to helpprevent rejection in organ transplantation.

[0005] Unfortunately, in addition to the desired therapeutic effects ofglucocorticoids, their use is associated with a number of adverseside-effects, some of which can be severe and life-threatening. Theseinclude alterations in fluid and electrolyte balance, edema, weightgain, hypertension, muscle weakness, development or aggravation ofdiabetes mellitus, and osteoporosis. Therefore, a compound thatexhibited a reduced side effect profile while maintaining the potentanti-inflammatory effects would be particularly desirable especiallywhen treating a chronic disease.

[0006] The effects of glucocorticoids are mediated at the cellular levelby the glucocorticoid receptor (R. H. Oakley and J. Cidlowski,Glucocorticoids, N. J. Goulding and R. J. Flowers (eds.), Boston:Birkhauser, 2001, pp. 55-80). The glucocorticoid receptor is a member ofa class of structurally related intracellular receptors that whencoupled with a ligand can function as a transcription factor thataffects gene expression (R. M. Evans, Science, 1988, 240, pp. 889-895).Other members of the family of steroid receptors include themineralocorticoid, progesterone, estrogen, and androgen receptors. Inaddition to the effects mentioned above for glucocorticoids, hormonesthat act on this receptor family have a profound influence on bodyhomeostasis, mineral metabolism, the stress response, and development ofsexual characteristics. Glucocorticoids, N. J. Goulding and R. J.Flowers (eds.), Boston: Birkhauser, 2001, is hereby incorporated byreference in its entirety to better describe the state of the art.

[0007] A molecular mechanism which accounts for the beneficialanti-inflammatory effects and the undesired side effects has beenproposed (e.g., S. Heck et al., EMBO J, 1994, 17, pp. 4087-4095; H. M.Reichardt et al., Cell, 1998, 93, pp. 531-541; F. Tronche et al., Curr.Opin. in Genetics and Dev., 1998, 8, pp. 532-538). Many of the metabolicand cardiovascular side effects are thought to be the result of aprocess called transactivation. In transactivation, the translocation ofthe ligand-bound glucocorticoid receptor to the nucleus is followed bybinding to glucocorticoid response elements (GREs) in the promoterregion of side-effect associated genes, for example phosphoenolpyruvatecarboxy kinase (PEPCK) in the case of increased glucose production. Theresult is an increased transcription rate of these genes which isbelieved to result, ultimately, in the observed side effects. Theanti-inflammatory effects are thought to be due to a process calledtransrepression. In general, transrepression is a process independent ofDNA binding that results from inhibition of NF-kB and AP-1-mediatedpathways, leading to down regulation of many inflammatory and immunemediators. Additionally, it is believed that a number of the observedside effects may be due to the cross-reactivity of the currentlyavailable glucocorticoids with other steroid receptors, particularly themineralocorticoid and progesterone receptors.

[0008] Thus it may be possible to discover ligands for theglucocorticoid receptor that are highly selective and, upon binding, candissociate the transactivation and transrepression pathways, providingtherapeutic agents with a reduced side effect profile. Assay systems todetermine effects on transactivation and transrepression have beendescribed (e.g., C. M. Bamberger and H. M. Schulte, Eur. J. Clin.Invest., 2000, 30 (suppl. 3), pp. 6-9). Selectivity for theglucocorticoid receptor may be determined by comparing the bindingaffinity for this receptor with that of other steroid family receptorsincluding those mentioned above.

[0009] Glucocorticoids also stimulate the production of glucose in theliver by a process called gluconeogenesis (J. E. Freidman et al, J.Biol. Chem., 1997, 272, 31475-31481) and it is believed that thisprocess is mediated by transactivation events. Increased glucoseproduction can exacerbate type II diabetes therefore a compound thatselectivity inhibited glucocorticoid mediated glucose production mayhave therapeutic utility in this indication.

[0010] Novel ligands for the glucocorticoid receptor have been describedin the scientific and patent literature. For example, PCT InternationalPublication No. WO 99/33786 discloses triphenylpropanamide compoundswith potential use in treating inflammatory diseases. PCT InternationalPublication No. WO 00/66522 describes non-steroidal compounds asselective modulators of the glucocorticoid receptor potentially usefulin treating metabolic and inflammatory diseases. PCT InternationalPublication No. WO 99/41256 describes tetracyclic modulators of theglucocorticoid receptor potentially useful in treating immune,autoimmune, and inflammatory diseases. U.S. Pat. No. 5,688,810 describesvarious non-steroidal compounds as modulators of glucocorticoid andother steroid receptors. PCT International Publication No. WO 99/63976describes a non-steroidal, liver-selective glucocorticoid antagonistpotentially useful in the treatment of diabetes. PCT InternationalPublication No. WO 00/32584 discloses non-steroidal compounds havinganti-inflammatory activity with dissociation between anti-inflammatoryand metabolic effects. PCT International Publication No. WO 98/54159describes non-steroidal cyclically substituted acylanilides with mixedgestagen and androgen activity. U.S. Pat. No. 4,880,839 describesacylanilides having progestational activity and EP 253503 disclosesacylanilides with antiandrogenic properties. PCT InternationalPublication No. WO 97/27852 describes amides that are inhibitors offarnesyl-protein transferase.

[0011] A compound that is found to interact with the glucocorticoidreceptor in a binding assay could be an agonist or an antagonist. Theagonist properties of the compound could be evaluated in thetransactivation or transrepression assays described above. Given theefficacy demonstrated by available glucocorticoid drugs in inflammatoryand immune diseases and their adverse side effects, there remains a needfor novel glucocorticoid receptor agonists with selectivity over othermembers of the steroid receptor family and a dissociation of thetransactivation and transrepression activities. Alternatively thecompound may be found to have antagonist activity. As mentioned above,glucocorticoids stimulate glucose production in the liver. Increasedglucose production induced by glucocorticoid excess can exacerbateexisting diabetes, or trigger latent diabetes. Thus a ligand for theglucocorticoid receptor that is found to be an antagonist may be usefulfor treating or preventing diabetes.

SUMMARY OF THE INVENTION

[0012] In a first general aspect, the instant invention is directed tocompounds of Formula (IA)

[0013] wherein:

[0014] R¹ is an aryl or heteroaryl group, each optionally independentlysubstituted with one to three substituent groups,

[0015] wherein each substituent group of R¹ is independently C₁-C₅alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl,aryl, heteroaryl, C₁-C₅ alkoxy, C₂-C₅ alkenyloxy, C₂-C₅ alkynyloxy,aryloxy, acyl, C₁-C₅ alkoxycarbonyl, C₁-C₅ alkanoyloxy, aminocarbonyl,C₁-C₅ alkylaminocarbonyl, C₁-C₅ dialkylaminocarbonyl, aminocarbonyloxy,C₁-C₅ alkylaminocarbonyloxy, C₁-₁C₅ dialkylaminocarbonyloxy, C₁-C₅alkanoylamino, C₁-C₅ alkoxycarbonylamino, C₁-C₅ alkylsulfonylamino,aminosulfonyl, C₁-C₅ alkylaminosulfonyl, C₁-C₅ dialkylaminosulfonyl,halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy,nitro, or amino wherein the nitrogen atom is optionally independentlymono- or di-substituted by C₁-C₅ alkyl or aryl; or ureido wherein eithernitrogen atom is optionally independently substituted with C₁-C₅ alkyl;or C₁-C₅ alkylthio wherein the sulfur atom is optionally oxidized to asulfoxide or sulfone;

[0016] wherein each substituent group of R¹ is optionally independentlysubstituted with one to three substituent groups selected from C₁-C₃alkyl, C₁-C₃ alkoxy, halogen, hydroxy, oxo, cyano or amino;

[0017] R² and R³ are each independently hydrogen or C₁-C₅ alkyl, or R²and R³ together with the carbon atom they are commonly attached to forma C₃-C₈ spiro cycloalkyl ring;

[0018] R⁴ is C₁-C₅ alkyl, C₂-C₅ alkenyl, or C₂-C₅ alkynyl, eachoptionally independently substituted with one to three substituentgroups,

[0019] wherein each substituent group of R⁴ is independently C₁-C₃alkyl, hydroxy, halogen, amino, or oxo; and

[0020] R⁵ is a heteroaryl group optionally independently substitutedwith one to three substituent groups,

[0021] wherein each substituent group of R⁵ is independently C₁-C₅alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl,aryl, heteroaryl, C₁-C₅ alkoxy, C₂-C₅ alkenyloxy, C₂-C₅ alkynyloxy,aryloxy, acyl, C₁-C₅ alkoxycarbonyl, C₁-C₅ alkanoyloxy, aminocarbonyl,C₁-C₅ alkylaminocarbonyl, C₁-C₅ dialkylaminocarbonyl, aminocarbonyloxy,C₁-C₅ alkylaminocarbonyloxy, C₁-C₅ dialkylaminocarbonyloxy, C₁-C₅alkanoylamino, C₁-C₅ alkoxycarbonylamino, C₁-C₅ alkylsulfonylamino,aminosulfonyl, C₁-C₅ alkylaminosulfonyl, C₁-C₅ dialkylaminosulfonyl,halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy,trifluoromethylthio, nitro, or amino wherein the nitrogen atom isoptionally independently mono- or di-substituted by C₁-C₅ alkyl; orureido wherein either nitrogen atom is optionally independentlysubstituted with C₁-C₅ alkyl; or C₁-C₅ alkylthio wherein the sulfur atomis optionally oxidized to a sulfoxide or sulfone,

[0022] wherein each substituent group of R⁵ is optionally independentlysubstituted with one to three substituent groups selected from C₁-C₃alkyl, C₁-C₃ alkoxy, halogen, hydroxy, oxo, cyano, amino, ortrifluoromethyl,

[0023] R⁶ and R⁷ are each independently hydrogen, C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, C₂₋₈ alkenyloxy, C₂₋₈ alkynyloxy,hydroxy, carbocyclyl, heterocyclyl, aryl, aryloxy, acyl, heteroaryl,carbocycle-C₁-C₈ alkyl, aryl-C₁-C₈ alkyl, aryl-C₁-C₈ haloalkyl,heterocyclyl-C₁-C₈ alkyl, heteroaryl-C₁-C₈ alkyl, carbocycle-C₂-C₈alkenyl, aryl-C₂-C₈ alkenyl, heterocyclyl-C₂-C₈ alkenyl,heteroaryl-C₂-C₈ alkenyl, or C₁-C₅ alkylthio wherein the sulfur atom isoxidized to a sulfoxide or sulfone, each optionally independentlysubstituted with one to three substituent groups,

[0024] wherein each substituent group of R⁶ and R⁷ are independentlyC₁-C₅ alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈ cycloalkyl, phenyl,C₁-C₅ alkoxy, phenoxy, C₁-C₅ alkanoyl, aroyl, C₁-C₅ alkoxycarbonyl,C₁-C₅ alkanoyloxy, aminocarbonyl, C₁-C₅ alkylaminocarbonyl, C₁-C₅dialkylaminocarbonyl, aminocarbonyloxy, C₁-C₅ alkylaminocarbonyloxy,C₁-C₅ dialkylaminocarbonyloxy, C₁-C₅ alkanoylamino, C₁-C₅alkoxycarbonylamino, C₁-C₅ alkylsulfonylamino, aminosulfonyl, C₁-C₅alkylaminosulfonyl, C₁-C₅ dialkylaminosulfonyl, halogen, hydroxy,carboxy, cyano, oxo, trifluoromethyl, trifluoromethoxy, nitro; or aminowherein the nitrogen atom is optionally independently mono- ordi-substituted by C₁-C₅ alkyl; or ureido wherein either nitrogen atom isoptionally independently substituted with C₁-C₅ alkyl; or C₁-C₅alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxideor sulfone;

[0025] or a tautomer, prodrug, solvate, or salt thereof.

[0026] Another aspect of the invention includes compounds of Formula(IA) above, wherein:

[0027] R¹ is phenyl, naphthyl, indanyl, indenyl, dihydrobenzofuranyl,benzofuranyl, chromanyl, dihydroindolyl, indolyl, dihydrobenzothienyl,benzothienyl, benzodioxolanyl, dihydrobenzoxazolyl, benzoxazolyl,benzisoxazolyl, benzpyrazolyl, benzimidazolyl, quinolinyl,isoquinolinyl, dihydroquinolinyl, dihydroisoquinolinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, thienyl, furanyl,pyrrolyl, pyridinyl, pyrimidinyl, or pyrazinyl each optionallyindependently substituted with one to three substituent groups,

[0028] wherein each substituent group of R¹ is independently C₁-C₃alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, C₂-C₃ alkenyloxy,C₁-C₃ alkanoyl, C₁-C₃ alkoxycarbonyl, C₁-C₃ alkanoyloxy, halogen,hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, orC₁-C₃ alkylthio wherein the sulfur atom is optionally oxidized to asulfoxide or sulfone;

[0029] wherein each substituent group of R¹ is independently optionallysubstituted with a substituent group selected from methyl, methoxy,halogen, hydroxy, oxo, cyano, or amino;

[0030] R² and R³ are each independently hydrogen or C₁-C₃ alkyl, or R²and R³ together with the carbon atom they are commonly attached to forma C₃-C₆ spiro cycloalkyl ring;

[0031] R⁴ is C₁-C₃ alkyl or C₂-C₃ alkenyl, each optionally independentlysubstituted with one to three substituent groups,

[0032] wherein each substituent group of R⁴ is independently methyl,hydroxy, fluoro, chloro, bromo, or oxo; and

[0033] R⁵ is an imidazolyl, pyridinyl, indolyl, azaindolyl,diazaindolyl, benzofuranyl, furanopyridinyl, furanopyrimidinyl,benzothienyl, thienopyridinyl, thienopyrimidinyl, benzoxazolyl,oxazolopyridinyl, benzothiazolyl, thiazolopyridinyl, benzimidazolyl,imidazolopyridinyl, quinolinyl, or isoquinolinyl group, each optionallyindependently substituted with one to three substituent groups,

[0034] wherein each substituent group of R⁵ is independently C₁-C₃alkyl, C₂-C₃ alkenyl, phenyl, C₁-C₃ alkoxy, methoxycarbonyl,aminocarbonyl, C₁-C₃ alkylaminocarbonyl, C₁-C₃ dialkylaminocarbonyl,heterocyclylcarbonyl, hydroxy, fluoro, chloro, bromo, cyano,trifluoromethyl, or C₁-C₃ alkylthio wherein the sulfur atom isoptionally oxidized to a sulfoxide or sulfone,

[0035] wherein each substituent group of R⁵ is optionally independentlysubstituted with a substituent group selected from methyl, methoxy,hydroxy, fluoro, chloro, bromo, oxo, or trifluoromethyl,

[0036] R⁶ and R⁷ are each independently hydrogen, C₁₋₅ alkyl, C₁₋₅alkoxy, C₂₋₅ alkenyl, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl, benzyl, cyclopropylethyl,cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, phenethyl, phenoxy,hydroxy or C₁-C₅ alkylthio wherein the sulfur atom is oxidized to asulfoxide or sulfone, each optionally independently substituted with oneto three substituent groups,

[0037] wherein each substituent group of R⁶ and R⁷ are independentlymethyl, methoxy, hydroxy, halogen, cyano, oxo or trifluoromethyl;

[0038] or a tautomer, prodrug, solvate, or salt thereof.

[0039] Yet another aspect of the invention is directed to compounds ofFormula (IA) above, wherein:

[0040] R¹ is thienyl, phenyl, naphthyl, pyridinyl, chromanyl,dihydrobenzofuranyl, or benzofuranyl, each optionally independentlysubstituted with one or two substituent groups,

[0041] wherein each substituent group of R¹ is independently methyl,ethyl, methoxy, ethoxy, fluoro, chloro, bromo, hydroxy, trifluoromethyl,trifluoromethoxy, oxo or cyano;

[0042] R² and R³ are each independently C₁-C₃ alkyl, or R² and R³together with the carbon atom they are commonly attached to form a spirocyclopropyl or cyclobutyl ring;

[0043] R⁴ is C₁-C₃ alkyl; and

[0044] R⁵ is a pyridinyl, indolyl, azaindolyl, benzofuranyl,furanopyridinyl, benzothienyl, thienopyridinyl, benzoxazolyl,benzimidazolyl, quinolinyl, or isoquinolinyl group, each optionallyindependently substituted with one to three substituent groups,

[0045] wherein each substituent group of R⁵ is independently methyl,phenyl, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, morpholinylcarbonyl, methoxy, hydroxy, fluoro,chloro, bromo, cyano, or trifluoromethyl,

[0046] R⁶ and R⁷ are each independently hydrogen, C₁₋₅ alkyl, benzyl,hydroxy or C₁-C₅ alkylthio wherein the sulfur atom is oxidized to asulfoxide or sulfone, each optionally independently substituted with oneto three substituent groups,

[0047] wherein each substituent group of R⁶ and R⁷ are independentlymethyl or oxo;

[0048] or a tautomer, prodrug, solvate, or salt thereof.

[0049] Yet another aspect of the invention is directed to compounds ofFormula (IA) above, wherein:

[0050] R¹ is phenyl, dihydrobenzofuranyl, benzofuranyl or pyridinylsubstituted with one or two substituent groups,

[0051] wherein each substituent group of R¹ is independently methyl,methoxy, fluoro, chloro, bromo, trifuoromethyl, trifluoromethoxy, cyanoor hydroxy;

[0052] R² and R³ are each independently C₁-C₃ alkyl;

[0053] R⁴ is CH₂; and

[0054] R⁵ is a pyridinyl, indolyl, azaindolyl, benzimidazolyl,quinolinyl, or isoquinolinyl group, each optionally independentlysubstituted with one to three substituent groups,

[0055] wherein each substituent group of R⁵ is independently methyl,fluoro, chloro, cyano or trifluoromethyl,

[0056] R⁶ and R⁷ are each independently hydrogen, methyl, ethyl, propyl,butyl, isobutyl, acetyl, formyl, methylsulfonyl or hydroxy,

[0057] or a tautomer, prodrug, solvate, or salt thereof.

[0058] Yet another aspect of the invention is directed to compounds ofFormula (IA) above, wherein:

[0059] R¹ is a pyridinyl, is a phenyl substituted with a fluoro, is aphenyl substituted with a methoxy group and a fluoro, is a phenylsubstituted with a hydroxy group and a fluoro, is a benzofuranyl group,is a dihydrobenzofuranyl group or is a dihydrobenzofuranyl groupsubstituted with a cyano group,

[0060] R² and R³ are each independently methyl;

[0061] R⁴ is CH₂; and

[0062] R⁵ is a quinolinyl, azaindolyl, pyridinyl, benzimidazolyl orindolyl, each optionally independently substituted with one to threesubstituent groups,

[0063] wherein each substituent group of R⁵ is independently methyl,fluoro, chloro, trifluoromethyl or cyano,

[0064] R⁶ and R⁷ are each independently hydrogen, methyl, ethyl, propyl,butyl, isobutyl, acetyl, formyl, methylsulfonyl or hydroxy,

[0065] or a tautomer, prodrug, solvate, or salt thereof.

[0066] Yet another aspect of the invention is directed to compounds ofFormula (IA) above, wherein:

[0067] R¹ is phenyl substituted with one or two substituent groups,

[0068] wherein each substituent group of R¹ is independently methoxy,fluoro, chloro, bromo or hydroxy;

[0069] or a tautomer, prodrug, solvate, or salt thereof.

[0070] Another aspect of the invention is directed to compounds ofFormula (IA) above, wherein:

[0071] R² and R³ together with the carbon atom they are commonlyattached to form a C₃-C₈ spiro cycloalkyl ring;

[0072] or a tautomer, prodrug, solvate, or salt thereof.

[0073] Another aspect of the invention is directed to compounds ofFormula (IA) above, wherein:

[0074] R² and R³ are each independently hydrogen or C₁-C₅ alkyl;

[0075] or a tautomer, prodrug, solvate, or salt thereof.

[0076] Another aspect of the invention is directed to compounds ofFormula (IA) above, wherein:

[0077] R² and R³ are each independently C₁-C₃ alkyl;

[0078] or a tautomer, prodrug, solvate, or salt thereof.

[0079] Another aspect of the invention is directed to compounds ofFormula (IA) above, wherein:

[0080] R⁴ is CH₂.

[0081] Another aspect of the invention is directed to compounds ofFormula (IA) above, wherein:

[0082] R⁵ is a pyridinyl, indolyl, quinolinyl or azaindolyl eachoptionally independently substituted with one to three substituentgroups,

[0083] wherein each substituent group of R⁵ is independently methyl,fluoro, chloro or cyano,

[0084] Another aspect of the invention is directed to compounds ofFormula (IA) above, wherein:

[0085] R⁶ and R⁷ are each independently hydrogen, methyl, propyl, butyl,isobutyl;

[0086] or a tautomer, prodrug, solvate, or salt thereof.

[0087] Another aspect of the invention is directed to compounds ofFormula (IA) above, wherein:

[0088] R¹ is phenyl, naphthyl, dihydrobenzofuranyl, or benzofuranyl,each optionally independently substituted with one to three substituentgroups,

[0089] wherein each substituent group of R¹ is independently C₁-C₃alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, C₂-C₃ alkenyloxy,C₂-C₃ alkynyloxy, C₁-C₃ alkanoyl, C₁-C₃ alkoxycarbonyl, C₁-C₃alkanoyloxy, halogen, hydroxy, carboxy, cyano, trifluoromethyl, nitro,or C₁-C₃ alkylthio wherein the sulfur atom is optionally oxidized to asulfoxide or sulfone; and

[0090] R² and R³ are each independently hydrogen or C₁-C₃ alkyl,

[0091] or a tautomer, prodrug, solvate, or salt thereof.

[0092] The following are representative compounds according to Formula(IA) of the invention: Comp. No. Compound Name Compound Structure 13-(5-Fluoro-2-methoxy- phenyl)-3-methyl-1- (pyridin-2-ylmethyl)-1-trifluoromethyl-butylamine

2 3-(5-Fluoro-2-methoxy- phenyl)-1-(1H-indol-2- ylmethyl)-3-methyl-1-trifluoromethyl-butylamine

3 1-(2,6-Dichloro-pyridin-4- ylmethyl)-3-(5-fluoro-2-methoxy-phenyl)-3-methyl- 1-trifluoromethyl- butylamine

4 1-(4,6-Dimethyl-pyridin-2- ylmethyl)-3-(5-fluoro-2-methoxy-phenyl)-3-methyl- 1-trifluoromethyl- butylamine

5 1-(2-Chloro-pyridin-4- ylmethyl)-3-(5-fluoro-2-methoxy-phenyl)-3-methyl- 1-trifluoromethyl- butylamine

6 3-(5-Fluoro-2-methyl- phenyl)-3-methyl-1-(3- methyl-1H-indol-2-ylmethyl)-1- trifluoromethyl-butylamine

7 3-(5-Fluoro-2-methoxy- phenyl)-3-methyl-1-(3- methyl-1H-indol-2-ylmethyl)-1- trifluoromethyl-butylamine

8 1-(6-Fluoro-1H-indol-2- ylmethyl)-3-(5-fluoro-2-methoxy-phenyl)-3-methyl- 1-trifluoromethyl- butylamine

9 3-(4-Fluoro-phenyl)-3- methyl-1-(3-methyl-1H- indol-2-ylmethyl)-1-trifluoromethyl-butylamine

10 3-Benzofuran-7-yl-1-(2,6- dichloro-pyridin-4- ylmethyl)-3-methyl-1-trifluoromethyl-butylamine

11 3-(2,3-Dihydro-benzofuran- 7-yl)-1-(6-fluoro-1H-indol-2-ylmethyl)-3-methyl-1- trifluoromethyl-butylamine

12 3-(5-Fluoro-2-methoxy- phenyl)-3-methyl-1- quinolin-4-ylmethyl-1-trifluoromethyl-butylamine

13 1-(2-Chloro-quinolin-4- ylmethyl)-3-(5-fluoro-2-methyl-phenyl)-3-methyl-1- trifluoromethyl-butylamine

14 3-(4-Fluoro-phenyl)-3- methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl- butylamine

15 7-[3-Amino-3-(1H- benzoimidazol-2-ylmethyl)-4,4,4-trifluoro-1,1-dimethyl- butyl]-2,3-dihydro-benzofuran-5-carbonitrile

16 1-(6-Fluoro-1H- benzoimidazol-2-ylmethyl)- 3-(5-fluoro-2-methyl-phenyl)-3-methyl-1- trifluoromethyl-butylamine

17 2-[3-Amino-3-(1H- benzoimidazol-2-ylmethyl)-4,4,4-trifluoro-1,1-dimethyl- butyl]-4-fluoro-phenol

18 1-(1H-Benzoimidazol-2- ylmethyl)-3-(4-fluoro- phenyl)-3-methyl-1-trifluoromethyl-butylamine

19 1-(1H-Indol-2-ylmethyl)-3- methyl-3-pyridin-3-yl-1-trifluoromethyl-butylamine

20 1-(1H-Benzoimidazol-2- ylmethyl)-3-methyl-3- pyridin-4-yl-1-trifluoromethyl-butylamine

21 3-Methyl-1-(3-methyl-1H- indol-2-ylmethyl)-3- pyridin-3-yl-1-trifluoromethyl-butylamine

22 1-(6-Fluoro-1H-indol-2- ylmethyl)-3-methyl-3- pyridin-3-yl-1-trifluoromethyl-butylamine

23 3-(2,3-Dihydro-benzofuran- 7-yl)-1-(1H-indol-2- ylmethyl)-3-methyl-1-trifluoromethyl-butylamine

24 [3-(5-Fluoro-2-methoxy- phenyl)-3-methyl-1-quinolin- 4-ylmethyl-1-trifluoromethyl-butyl]- methyl-amine

25 Ethyl-[3-(5-fluoro-2- methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1- trifluoromethyl-butyl]-amine

26 [3-(5-Fluoro-2-methoxy- phenyl)-3-methyl-1-quinolin- 4-ylmethyl-1-trifluoromethyl-butyl]- propyl-amine

27 [3-(5-Fluoro-2-methoxy- phenyl)-3-methyl-1-quinolin- 4-ylmethyl-1-trifluoromethyl-butyl]- isobutyl-amine

28 Butyl-[3-(5-fluoro-2- methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1- trifluoromethyl-butyl]-amine

29 [3-(5-Fluoro-2-methoxy- phenyl)-3-methyl-1-quinolin- 4-ylmethyl-1-trifluoromethyl-butyl]- dimethyl-amine

30 N-[3-(5-Fluoro-2-methoxy- phenyl)-3-methyl-1-quinolin- 4-ylmethyl-1-trifluoromethyl-butyl]- acetamide

31 N-[3-(5-Fluoro-2-methoxy- phenyl)-3-methyl-1-quinolin- 4-ylmethyl-1-trifluoromethyl-butyl]- formamide

32 N-[3-(5-Fluoro-2-methoxy- phenyl)-3-methyl-1-quinolin- 4-ylmethyl-1-trifluoromethyl-butyl]- methanesulfonamide

33 1-(2,6-Dimethyl-pyridin-4- ylmethyl)-3-(5-fluoro-2-methoxy-phenyl)-3-methyl- 1-trifluoromethyl-butylamine

34 3-(5-Fluoro-2-methoxy- phenyl)-3-methyl-1-(1H-pyrrolo[2,3-c]pyridin-2- ylmethyl)-1-trifluoromethyl- butylamine

35 2-[2-Amino-4-(5-fluoro-2- methoxy-phenyl)-4-methyl-2-trifluoromethyl-pentyl]-4- methyl-1H-indole-6- carbonitrile

36 N-[3-(5-Fluoro-2-methoxy- phenyl)-3-methyl-1-quinolin- 4-ylmethyl-1-trifluoromethyl-butyl]- hydroxylamine

37 2-(3-Amino-4,4,4-trifluoro- 1,1-dimethyl-3-quinolin-4-ylmethyl-butyl)-4-fluoro- phenol

[0093] and the tautomers, prodrugs, solvates, or salts thereof.

[0094] Selected compounds of formula (IA) include the following:

[0095]3-(5-Fluoro-2-methoxy-phenyl)-1-(1H-indol-2-ylmethyl)-3-methyl-1-trifluoromethyl-butylamine;

[0096]3-(5-Fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butylamine;

[0097][3-(5-Fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butyl]-isobutyl-amine;

[0098][3-(5-Fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butyl]-propyl-amine;

[0099]Butyl-[3-(5-fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butyl]-amine;and

[0100][3-(5-Fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butyl]-methyl-amine;

[0101] or a tautomer, prodrug, solvate, or salt thereof.

[0102] In a second general aspect, the instant invention is directed tocompounds of Formula (IB)

[0103] wherein:

[0104] R¹ is an aryl or heteroaryl group, each optionally independentlysubstituted with one to three substituent groups,

[0105] wherein each substituent group of R¹ is independently C₁-C₅alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl,aryl, heteroaryl, C₁-C₅ alkoxy, C₂-C₅ alkenyloxy, C₂-C₅ alkynyloxy,aryloxy, acyl, C₁-C₅ alkoxycarbonyl, C₁-C₅ alkanoyloxy, aminocarbonyl,C₁-C₅ alkylaminocarbonyl, C₁-C₅ dialkylaminocarbonyl, aminocarbonyloxy,C₁-C₅ alkylaminocarbonyloxy, C₁-C5 dialkylaminocarbonyloxy, C₁-C₅alkanoylamino, C₁-C₅ alkoxycarbonylamino, C₁-C₅ alkylsulfonylamino,aminosulfonyl, C₁-C₅ alkylaminosulfonyl, C₁-C₅ dialkylaminosulfonyl,halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy,nitro, or amino wherein the nitrogen atom is optionally independentlymono- or di-substituted by C₁-C₅ alkyl or aryl; or ureido wherein eithernitrogen atom is optionally independently substituted with C₁-C₅ alkyl;or C₁-C₅ alkylthio wherein the sulfur atom is optionally oxidized to asulfoxide or sulfone;

[0106] wherein each substituent group of R¹ is independently optionallysubstituted with one to three substituent groups selected from C₁-C₃alkyl, C₁-C₃ alkoxy, halogen, hydroxy, oxo, cyano or amino.

[0107] R² and R³ are each independently hydrogen or C₁-C₅ alkyl, or R²and R³ together with the carbon atom they are commonly attached to forma C₃-C₈ spiro cycloalkyl ring;

[0108] R⁴ is C₁-C₅ alkyl, C₂-C₅ alkenyl, or C₂-C₅ alkynyl, eachoptionally independently substituted with one to three substituentgroups,

[0109] wherein each substituent group of R⁴ is independently C₁-C₃alkyl, hydroxy, halogen, amino, or oxo;

[0110] R⁵ is a heteroaryl group optionally independently substitutedwith one to three substituent groups,

[0111] wherein each substituent group of R⁵ is independently C₁-C₅alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl,aryl, heteroaryl, C₁-C₅ alkoxy, C₂-C₅ alkenyloxy, C₂-C₅ alkynyloxy,aryloxy, acyl, C₁-C₅ alkoxycarbonyl, C₁-C₅ alkanoyloxy, aminocarbonyl,C₁-C₅ alkylaminocarbonyl, C₁-C5 dialkylaminocarbonyl, aminocarbonyloxy,C₁-C₅ alkylaminocarbonyloxy, C₁-C₅ dialkylaminocarbonyloxy, C₁-C₅alkanoylamino, C₁-C₅ alkoxycarbonylamino, C₁-C₅ alkylsulfonylamino,aminosulfonyl, C₁-C₅ alkylaminosulfonyl, C₁-C₅ dialkylaminosulfonyl,halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy,trifluoromethylthio, nitro, or amino wherein the nitrogen atom isoptionally independently mono- or di-substituted by C₁-C₅ alkyl; orureido wherein either nitrogen atom is optionally independentlysubstituted with C₁-C₅ alkyl; or C₁-C₅ alkylthio wherein the sulfur atomis optionally oxidized to a sulfoxide or sulfone,

[0112] wherein each substituent group of R⁵ is optionally independentlysubstituted with one to three substituent groups selected from C₁-C₃alkyl, C₁-C₃ alkoxy, halogen, hydroxy, oxo, cyano, amino, ortrifluoromethyl;

[0113] R⁶ and R⁷ are each independently hydrogen, C₁₋₈ alkyl, C₂₋₈alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, C₂₋₈ alkenyloxy, C₂₋₈ alkynyloxy,hydroxy, carbocyclyl, heterocyclyl, aryl, aryloxy, acyl, heteroaryl,carbocycle-C₁-C₈ alkyl, aryl-C₁-C₈ alkyl, aryl-C₁-C₈ haloalkyl,heterocyclyl-C₁-C₈ alkyl, heteroaryl-C₁-C₈ alkyl, carbocycle-C₂-C₈alkenyl, aryl-C₂-C₈ alkenyl, heterocyclyl-C₂-C₈ alkenyl,heteroaryl-C₂-C₈ alkenyl, or C₁-C₅ alkylthio wherein the sulfur atom isoxidized to a sulfoxide or sulfone, each optionally independentlysubstituted with one to three substituent groups,

[0114] wherein each substituent group of R⁶ and R⁷ are independentlyC₁-C₅ alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈ cycloalkyl, phenyl,C₁-C₅ alkoxy, phenoxy, C₁-C₅ alkanoyl, aroyl, C₁-C₅ alkoxycarbonyl,C₁-C₅ alkanoyloxy, aminocarbonyl, C₁-C₅ alkylaminocarbonyl, C₁-C₅dialkylaminocarbonyl, aminocarbonyloxy, C₁-C₅ alkylaminocarbonyloxy,C₁-C₅ dialkylaminocarbonyloxy, C₁-C₅ alkanoylamino, C₁-C₅alkoxycarbonylamino, C₁-C₅ alkylsulfonylamino, aminosulfonyl, C₁-C₅alkylaminosulfonyl, C₁-C₅ dialkylaminosulfonyl, halogen, hydroxy,carboxy, cyano, oxo, trifluoromethyl, trifluoromethoxy, nitro; or aminowherein the nitrogen atom is optionally independently mono- ordi-substituted by C₁-C₅ alkyl; or ureido wherein either nitrogen atom isoptionally independently substituted with C₁-C₅ alkyl; or C₁-C₅alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxideor sulfone;

[0115] R⁸ is C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, carbocycle,heterocyclyl, aryl, heteroaryl, carbocycle-C₁-C₈ alkyl, aryl-C₁-C₈alkyl, aryl-C₁-C₈ haloalkyl, heterocyclyl-C₁-C₈ alkyl, heteroaryl-C₁-C₈alkyl, carbocycle-C₂-C₈ alkenyl, aryl-C₂-C₈ alkenyl, heterocyclyl-C₂-C₈alkenyl, or heteroaryl-C₂-C₈ alkenyl, each optionally independentlysubstituted with one to three substituent groups,

[0116] wherein each substituent group of R⁸ is independently C₁-C₅alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈ cycloalkyl, phenyl, C₁-C₅alkoxy, phenoxy, C₁-C₅ alkanoyl, aroyl, C₁-C₅ alkoxycarbonyl, C₁-C₅alkanoyloxy, aminocarbonyloxy, C₁-C₅ alkylaminocarbonyloxy, C₁-C₅dialkylaminocarbonyloxy, aminocarbonyl, C₁-C₅ alkylaminocarbonyl, C₁-C₅dialkylaminocarbonyl, C₁-C₅ alkanoylamino, C₁-C₅ alkoxycarbonylamino,C₁-C₅ alkylsulfonylamino, aminosulfonyl, C₁-C₅ alkylaminosulfonyl, C₁-C₅dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, oxo,trifluoromethyl, nitro; or amino wherein the nitrogen atom is optionallyindependently mono- or di-substituted by C₁-C₅ alkyl; or ureido whereineither nitrogen atom is optionally independently substituted with C₁-C₅alkyl; or C₁-C₅ alkylthio wherein the sulfur atom is optionally oxidizedto a sulfoxide or sulfone;

[0117] wherein R⁸ cannot be trifluoromethyl;

[0118] or a tautomer, prodrug, solvate, or salt thereof.

[0119] Another aspect of the invention is directed to compounds ofFormula (IB) above, wherein:

[0120] R¹ is phenyl, naphthyl, indanyl, indenyl, dihydrobenzofuranyl,benzofuranyl, chromanyl, dihydroindolyl, indolyl, dihydrobenzothienyl,benzothienyl, benzodioxolanyl, dihydrobenzoxazolyl, benzoxazolyl,benzisoxazolyl, benzpyrazolyl, benzimidazolyl, dihydroquinolinyl,quinolinyl, dihydroisoquinolinyl, isoquinolinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, furanyl, thienyl, pyrrolyl, pyridinyl,pyrazinyl, or pyrimidinyl, each optionally independently substitutedwith one to three substituent groups,

[0121] wherein each substituent group of R¹ is independently C₁-C₃alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, C₂-C₃ alkenyloxy,C₁-C₃ alkanoyl, C₁-C₃ alkoxycarbonyl, C₁-C₃ alkanoyloxy, halogen,hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, orC₁-C₃ alkylthio wherein the sulfur atom is optionally oxidized to asulfoxide or sulfone;

[0122] wherein each substituent group of R¹ is optionally independentlysubstituted with a substituent group selected from methyl, methoxy,halogen, hydroxy, oxo, cyano, or amino;

[0123] R² and R³ are each independently hydrogen or C₁-C₃ alkyl, or R²and R³ together with the carbon atom they are commonly attached to forma C₃-C₆ spiro cycloalkyl ring;

[0124] R⁴ is C₁-C₃ alkyl or C₂-C₃ alkenyl, each optionally independentlysubstituted with one to three substituent groups,

[0125] wherein each substituent group of R⁴ is independently methyl,hydroxy, fluoro, chloro, bromo, or oxo;

[0126] R⁵ is an imidazolyl, pyridinyl, indolyl, azaindolyl,diazaindolyl, benzofuranyl, furanopyridinyl, furanopyrimidinyl,benzothienyl, thienopyridinyl, thienopyrimidinyl, benzoxazolyl,oxazolopyridinyl, benzothiazolyl, thiazolopyridinyl, benzimidazolyl,imidazolopyridinyl, quinolinyl, or isoquinolinyl group, each optionallyindependently substituted with one to three substituent groups,

[0127] wherein each substituent group of R⁵ is independently C₁-C₃alkyl, C₂-C₃ alkenyl, phenyl, C₁-C₃ alkoxy, methoxycarbonyl,aminocarbonyl, C₁-C₃ alkylaminocarbonyl, C₁-C₃ dialkylaminocarbonyl,heterocyclylcarbonyl, hydroxy, fluoro, chloro, bromo, cyano,trifluoromethyl, or C₁-C₃ alkylthio wherein the sulfur atom isoptionally oxidized to a sulfoxide or sulfone,

[0128] wherein each substituent group of R⁵ is optionally independentlysubstituted with a substituent group selected from methyl, methoxy,hydroxy, fluoro, chloro, bromo, oxo or trifluoromethyl,

[0129] R⁶ and R⁷ are each independently hydrogen, C₁₋₅ alkyl, C₁₋₅alkoxy, C₂₋₅ alkenyl, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl, benzyl, cyclopropylethyl,cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, phenethyl, phenoxy,hydroxy or C₁-C₅ alkylthio wherein the sulfur atom is oxidized to asulfoxide or sulfone, each optionally independently substituted with oneto three substituent groups,

[0130] wherein each substituent group of R⁶ and R⁷ are independentlymethyl, methoxy, halogen, hydroxy, cyano, oxo or trifluoromethyl;

[0131] R⁸ is C₁₋₅ alkyl, C₂₋₅ alkenyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, phenyl, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl, benzyl, cyclopentylethyl,cyclohexylethyl, phenethyl, or phenyl-difluoromethyl, each optionallyindependently substituted with one to three substituent groups,

[0132] wherein each substituent group of R⁸ is independently methyl,methoxy, hydroxy, halogen, cyano, or trifluoromethyl;

[0133] wherein R⁸ cannot be trifluoromethyl;

[0134] or a tautomer, prodrug, solvate, or salt thereof.

[0135] Yet another aspect of the invention is directed to compounds ofFormula (IB) above, wherein:

[0136] R¹ is phenyl, thienyl, naphthyl, chromanyl, pyridinyl,dihydrobenzofuranyl, or benzofuranyl, each optionally independentlysubstituted with one or two substituent groups,

[0137] wherein each substituent group of R¹ is independently methyl,ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, fluoro,chloro, bromo, hydroxy, oxo or cyano;

[0138] R² and R³ are each independently C₁-C₃ alkyl, or R² and R³together with the carbon atom they are commonly attached to form a spirocyclopropyl or cyclobutyl ring;

[0139] R⁴ is C₁-C₃ alkyl;

[0140] R⁵ is a pyridinyl, indolyl, azaindolyl, benzofuranyl,furanopyridinyl, benzothienyl, thienopyridinyl, benzoxazolyl,benzimidazolyl, quinolinyl, or isoquinolinyl group, each optionallyindependently substituted with one to three substituent groups,

[0141] wherein each substituent group of R⁵ is independently methyl,phenyl, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl,dimethylaminocarbonyl, morpholinylcarbonyl, methoxy, hydroxy, fluoro,chloro, bromo, cyano, or trifluoromethyl,

[0142] R⁶ and R⁷ are each independently hydrogen, C₁₋₅ alkyl, benzyl,hydroxy or C₁-C₅ alkylthio wherein the sulfur atom is oxidized to asulfoxide or sulfone, each optionally independently substituted with oneto three substituent groups,

[0143] wherein each substituent group of R⁶ and R⁷ are independentlymethyl, or oxo; and

[0144] R⁸ is C₁₋₅ alkyl, cyclopropyl, cyclopentylmethyl,cyclohexylmethyl or benzyl,

[0145] or a tautomer, prodrug, solvate, or salt thereof.

[0146] Yet another aspect of the invention is directed to compounds ofFormula (IB) above, wherein:

[0147] R¹ is phenyl, dihydrobenzofuranyl, benzofuranyl or pyridinylsubstituted with one or two substituent groups,

[0148] wherein each substituent group of R¹ is independently methyl,methoxy, fluoro, chloro, bromo, trifuoromethyl, trifluoromethoxy, cyanoor hydroxy;

[0149] R² and R³ are each independently C₁-C₃ alkyl;

[0150] R⁴ is CH₂;

[0151] R⁵ is a pyridinyl, indolyl, azaindolyl, benzimidazolyl,quinolinyl, or isoquinolinyl group, each optionally independentlysubstituted with one to three substituent groups,

[0152] wherein each substituent group of R⁵ is independently methyl,fluoro, chloro, cyano or trifluoromethyl,

[0153] R⁶ and R⁷ are each independently hydrogen, methyl, ethyl, propyl,butyl, isobutyl, acetyl, formyl, methylsulfonyl or hydroxy, and

[0154] R⁸ is methyl, ethyl, n-propyl, i-propyl, cyclopropyl,cyclopentylmethyl or cyclohexylmethyl;

[0155] or a tautomer, prodrug, solvate, or salt thereof.

[0156] Yet another aspect of the invention is directed to compounds ofFormula (IB) above, wherein:

[0157] R¹ is phenyl substituted with a methoxy group and a fluoro, or isa phenyl substituted with a hydroxy group and a fluoro;

[0158] R² and R³ are each independently methyl;

[0159] R⁴ is CH₂;

[0160] R⁵ is a quinolinyl, azaindolyl, pyridinyl or indolyl, eachoptionally independently substituted with one to three substituentgroups,

[0161] wherein each substituent group of R⁵ is independently methyl,fluoro, chloro, trifluoromethyl or cyano;

[0162] R⁶ and R⁷ are each independently hydrogen, methyl or isobutyl;and

[0163] R⁸ is methyl, cyclopropyl, or cyclohexylmethyl;

[0164] or a tautomer, prodrug, solvate, or salt thereof.

[0165] Yet another aspect of the invention is directed to compounds ofFormula (IB) above, wherein:

[0166] R¹ is phenyl substituted with one or two substituent groups,

[0167] wherein each substituent group of R¹ is independently methoxy,fluoro, chloro, bromo or hydroxy;

[0168] or a tautomer, prodrug, solvate, or salt thereof.

[0169] Yet another aspect of the invention is directed to compounds ofFormula (IB) above, wherein:

[0170] R² and R³ together with the carbon atom they are commonlyattached to form a C₃-C₈ spiro cycloalkyl ring;

[0171] or a tautomer, prodrug, solvate, or salt thereof.

[0172] Yet another aspect of the invention is directed to compounds ofFormula (IB) above, wherein:

[0173] R² and R³ are each independently hydrogen or C₁-C₅ alkyl;

[0174] or a tautomer, prodrug, solvate, or salt thereof.

[0175] Yet another aspect of the invention is directed to compounds ofFormula (IB) above, wherein:

[0176] R² and R³ are each independently C₁-C₃ alkyl;

[0177] or a tautomer, prodrug, solvate, or salt thereof.

[0178] Yet another aspect of the invention is directed to compounds ofFormula (IB) above, wherein:

[0179] R⁴ is CH₂.

[0180] Yet another aspect of the invention is directed to compounds ofFormula (IB) above, wherein:

[0181] R⁵ is a quinolinyl, azaindolyl, pyridinyl or indolyl, eachoptionally independently substituted with one to three substituentgroups,

[0182] wherein each substituent group of R⁵ is independently methyl,fluoro, chloro or cyano;

[0183] or a tautomer, prodrug, solvate, or salt thereof.

[0184] Yet another aspect of the invention is directed to compounds ofFormula (IB) above, wherein:

[0185] R⁶ and R⁷ are each independently hydrogen;

[0186] or a tautomer, prodrug, solvate, or salt thereof.

[0187] Yet another aspect of the invention is directed to compounds ofFormula (IB) above, wherein:

[0188] R⁸ is methyl, cyclohexylmethyl or cyclopropyl;

[0189] or a tautomer, prodrug, solvate, or salt thereof.

[0190] Yet another aspect of the invention is directed to compounds ofFormula (IB) above, wherein:

[0191] R¹ is phenyl, naphthyl, dihydrobenzofuranyl, furanyl, orbenzofuranyl, each optionally independently substituted with one tothree substituent groups,

[0192] wherein each substituent group of R¹ is independently C₁-C₃alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, C₂-C₃ alkenyloxy,C₁-C₃ alkanoyl, C₁-C₃ alkoxycarbonyl, C₁-C₃ alkanoyloxy, halogen,hydroxy, carboxy, cyano, trifluoromethyl, nitro, or C₁-C₃ alkylthiowherein the sulfur atom is optionally oxidized to a sulfoxide orsulfone; and

[0193] R² and R³ are each independently hydrogen or C₁-C₃ alkyl,

[0194] or a tautomer, prodrug, solvate, or salt thereof.

[0195] The following are representative compounds according to Formula(IB) of the invention: Comp. No. Compound Name Compound Structure 381-(2,6-Dichloro-pyridin-4- ylmethyl)-3-(5-fluoro-2- methoxy-phenyl)-1,3-dimethyl-butylamine

39 1-Ethyl-3-(5-fluoro-2- methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl- butylamine

40 1-Cyclohexylmethyl-3-(5- fluoro-2-methoxy-phenyl)-1-(1H-indol-2-ylmethyl)-3- methyl-butylamine

41 1-(2-Chloro-quinolin-4- ylmethyl)-1-cyclopentyl-3-(5-fluoro-2-methoxy- phenyl)-3-methyl-butylamine

42 1-(2-Chloro-pyridin-4- ylmethyl)-1- cyclopentylmethyl-3-(5-fluoro-2-methoxy-phenyl)-3- methyl-butylamine

43 3-(5-Fluoro-2-methoxy- phenyl)-1,3-dimethyl-1- quinolin-4-ylmethyl-butylamine

44 1-Cyclopropyl-3-(5-fluoro-2- methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl- butylamine

45 3-(5-Fluoro-2-methoxy- phenyl)-1,3-dimethyl-1-(1H-pyrrolo[2,3-c]pyridin-2- ylmethyl)-butylamine

46 1-Cyclopropyl-3-(5-fluoro-2- methoxy-phenyl)-3-methyl-1-(1H-pyrrolo[2,3-c]pyridin-2- ylmethyl)-butylamine

47 2-[3-Amino-1,1,3-trimethyl-4- (1H-pyrrolo[2,3-c]pyridin-2-yl)-butyl]-4-fluoro-phenol

48 2-[2-Amino-4-(5-fluoro-2- methoxy-phenyl)-2,4-dimethyl-pentyl]-4-methyl- 1H-indole-6-carbonitrile

[0196] and the tautomers, prodrugs, solvates, or salts thereof.

[0197] Another aspect of the invention is directed to the methods formaking the compounds according to the invention by the methods asdescribed herein.

[0198] In another aspect of the invention, the compounds according tothe invention are formulated into pharmaceutical compositions comprisingan effective amount, preferably a pharmaceutically effective amount, ofa compound according to the invention or a tautomer, prodrug, solvate,or salt thereof, and a pharmaceutically acceptable excipient or carrier.

[0199] The invention also provides a method of modulating theglucocorticoid receptor function in a patient, the method comprisingadministering to the patient an effective amount of a compound accordingto the invention or a tautomer, prodrug, solvate, or salt thereof.

[0200] The invention further provides a method of treating adisease-state or condition mediated by the glucocorticoid receptorfunction in a patient in need of such treatment, the method comprisingadministering to the patient an effective amount of a pharmaceuticallyacceptable compound according to the invention or a tautomer, prodrug,solvate, or salt thereof.

[0201] In addition, the invention also provides a method of treating adisease-state or condition selected from: type II diabetes, obesity,cardiovascular diseases, hypertension, arteriosclerosis, neurologicaldiseases, adrenal and pituitary tumors, and glaucoma, in a patient inneed of such treatment, the method comprising administering to thepatient an effective amount of a pharmaceutically acceptable compoundaccording to the invention or a tautomer, prodrug, solvate, or saltthereof.

[0202] The invention provides a method of treating a diseasecharacterized by inflammatory, allergic, or proliferative processes, ina patient in need of such treatment, the method comprising administeringto the patient an effective amount of a pharmaceutically acceptablecompound according to the invention or a tautomer, prodrug, solvate, orsalt thereof. In a preferred embodiment of the invention, the diseasecharacterized by inflammatory, allergic, or proliferative processes isselected from: (i) lung diseases; (ii) rheumatic diseases or autoimmunediseases or joint diseases; (iii) allergic diseases; (iv) vasculitisdiseases; (v) dermatological diseases; (vi) renal diseases; (vii)hepatic diseases; (viii) gastrointestinal diseases; (ix) proctologicaldiseases; (x) eye diseases; (xi) diseases of the ear, nose, and throat(ENT) area; (xii) neurological diseases; (xiii) blood diseases; (xiv)tumor diseases; (xv) endocrine diseases; (xvi) organ and tissuetransplantations and graft-versus-host diseases; (xvii) severe states ofshock; (xviii) substitution therapy; and (xix) pain of inflammatorygenesis. In another preferred embodiment of the invention, the diseasecharacterized by inflammatory, allergic, or proliferative processes isselected from: type I diabetes, osteoarthritis, Guillain-Barre syndrome,restenosis following percutaneous transluminal coronary angioplasty,Alzheimer disease, acute and chronic pain, atherosclerosis, reperfusioninjury, bone resorption diseases, congestive heart failure, myocardialinfarction, thermal injury, multiple organ injury secondary to trauma,acute purulent meningitis, necrotizing enterocolitis, and syndromesassociated with hemodialysis, leukopheresis, and granulocytetransfusion.

[0203] The invention further provides methods of treating thedisease-states or conditions mentioned above, in a patient in need ofsuch treatment, the methods comprising sequentially or simultaneouslyadministering to the patient: (a) an effective amount of apharmaceutically acceptable compound according to the present inventionor a tautomer, prodrug, solvate, or salt thereof; and (b) apharmaceutically acceptable glucocorticoid.

[0204] The invention further provides a method of assaying theglucocorticoid receptor function in a sample, comprising: (a) contactingthe sample with a selected amount of a compound according to theinvention or a tautomer, prodrug, solvate, or salt thereof; and (b)detecting the amount of the compound according to the invention or atautomer, prodrug, solvate, or salt thereof bound to glucocorticoidreceptors in the sample. In a preferred embodiment of the invention, thecompound according to the invention or a tautomer, prodrug, solvate, orsalt thereof is labeled with a detectable marker selected from: aradiolabel, fluorescent tag, a chemiluminescent tag, a chromophore, anda spin label.

[0205] The invention also provides a method of imaging theglucocorticoid receptor distribution in a sample or patient, the methodcomprising: (a) contacting the sample or administering to a patient acompound according to the invention or a tautomer, prodrug, solvate, orsalt thereof having a detectable marker; (b) detecting the spatialdistribution and amount of the compound according to the invention or atautomer, prodrug, solvate, or salt thereof having a detectable markerbound to glucocorticoid receptors in the sample or patient using animaging means to obtain an image; and (c) displaying an image of thespatial distribution and amount of the compound according to theinvention or a tautomer, prodrug, solvate, or salt thereof having adetectable marker bound to glucocorticoid receptors in the sample. In apreferred embodiment of the invention, the imaging means is selectedfrom: radioscintigraphy, nuclear magnetic resonance imaging (MRI),computed tomography (CT scan), or positron emission tomography (PET).

[0206] The invention also provides a kit for the in vitro diagnosticdetermination of the glucocorticoid receptor function in a sample,comprising: (a) a diagnostically effective amount of a compoundaccording to the invention or a tautomer, prodrug, solvate, or saltthereof; and (b) instructions for use of the diagnostic kit.

DETAILED DESCRIPTION OF THE INVENTION

[0207] Definition of Terms and Conventions Used

[0208] Terms not specifically defined herein should be given themeanings that would be given to them by one of skill in the art in lightof the disclosure and the context. As used in the specification andappended claims, however, unless specified to the contrary, thefollowing terms have the meaning indicated and the following conventionsare adhered to.

[0209] A. Chemical Nomenclature, Terms, and Conventions

[0210] In the groups, radicals, or moieties defined below, the number ofcarbon atoms is often specified preceding the group, for example, C₁-C₁₀alkyl means an alkyl group or radical having 1 to 10 carbon atoms. Theterm “lower” applied to any carbon-containing group means a groupcontaining from 1 to 8 carbon atoms, as appropriate to the group (i.e.,a cyclic group must have at least 3 atoms to constitute a ring). Ingeneral, for groups comprising two or more subgroups, the last namedgroup is the radical attachment point, for example, “alkylaryl” means amonovalent radical of the formula Alk-Ar-, while “arylalkyl” means amonovalent radical of the formula Ar-Alk- (where Alk is an alkyl groupand Ar is an aryl group). Furthermore, the use of a term designating amonovalent radical where a divalent radical is appropriate shall beconstrued to designate the respective divalent radical and vice versa.Unless otherwise specified, conventional definitions of terms controland conventional stable atom valences are presumed and achieved in allformulas and groups.

[0211] The terms “alkyl” or “alkyl group” mean a branched orstraight-chain saturated aliphatic hydrocarbon monovalent radical. Thisterm is exemplified by groups such as methyl, ethyl, n-propyl,1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl(tert-butyl), and the like. It may be abbreviated “Alk”.

[0212] The terms “alkenyl” or “alkenyl group” mean a branched orstraight-chain aliphatic hydrocarbon monovalent radical containing atleast one carbon-carbon double bond. This term is exemplified by groupssuch as ethenyl, propenyl, n-butenyl, isobutenyl, 3-methylbut-2-enyl,n-pentenyl, heptenyl, octenyl, decenyl, and the like.

[0213] The terms “alkynyl” or “alkynyl group” mean a branched orstraight-chain aliphatic hydrocarbon monovalent radical containing atleast one carbon-carbon triple bond. This term is exemplified by groupssuch as ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl,n-pentynyl, beptynyl, octynyl, decynyl, and the like.

[0214] The terms “alkylene” or “alkylene group” mean a branched orstraight-chain saturated aliphatic hydrocarbon divalent radical havingthe specified number of carbon atoms. This term is exemplified by groupssuch as methylene, ethylene, propylene, n-butylene, and the like, andmay alternatively and equivalently be denoted herein as -(alkyl)-.

[0215] The terms “alkenylene” or “alkenylene group” mean a branched orstraight-chain aliphatic hydrocarbon divalent radical having thespecified number of carbon atoms and at least one carbon-carbon doublebond. This term is exemplified by groups such as ethenylene,propenylene, n-butenylene, and the like, and may alternatively andequivalently be denoted herein as -(alkylenyl)-.

[0216] The terms “alkynylene” or “alkynylene group” mean a branched orstraight-chain aliphatic hydrocarbon divalent radical containing atleast one carbon-carbon triple bond. This term is exemplified by groupssuch as ethynylene, propynylene, n-butynylene, 2-butynylene,3-metbylbutynylene, n-pentynylene, heptynylene, octynylene, decynylene,and the like, and may alternatively and equivalently be denoted hereinas -(alkynyl)-.

[0217] The terms “alkoxy” or “alkoxy group” mean a monovalent radical ofthe formula AlkO—, where Alk is an alkyl group. This term is exemplifiedby groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,sec-butoxy, tert-butoxy, pentoxy, and the like.

[0218] The terms “aryloxy”, “aryloxy group”, mean a monovalent radicalof the formula ArO—, where Ar is aryl. This term is exemplified bygroups such as phenoxy, naphthoxy, and the like.

[0219] The term “oxo” means a double-bonded divalent oxygen radical ofthe formula (═O), For instance, one example of an alkyl groupsubstituted by an “oxo” would be a group of the formula Alk-C(O)-Alk,wherein each Alk is an alkyl.

[0220] The terms “alkylcarbonyl”, “alkylcarbonyl group”, “alkanoyl”, or“alkanoyl group” mean a monovalent radical of the formula AlkC(O)—,where Alk is alkyl or hydrogen.

[0221] The terms “arylcarbonyl”, “arylcarbonyl group”, “aroyl” or “aroylgroup” mean a monovalent radical of the formula ArC(O)—, where Ar isaryl.

[0222] The terms “acyl” or “acyl group” mean a monovalent radical of theformula RC(O)—, where R is a substituent selected from hydrogen or anorganic substituent. Exemplary substituents include alkyl, aryl,arylalkyl, cycloalkyl, heterocyclyl, heteroaryl, heteroarylalkyl, andthe like. As such, the terms comprise alkylcarbonyl groups andarylcarbonyl groups.

[0223] The terms “acylamino” or “acylamino group” mean a monovalentradical of the formula RC(O)N(R)—, where each R is a substituentselected from hydrogen or a substituent group.

[0224] The terms “alkoxycarbonyl” or “alkoxycarbonyl group” mean amonovalent radical of the formula AlkO—C(O)—, where Alk is alkyl.Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl,tert-butyloxycarbonyl, and the like.

[0225] The terms “alkylaminocarbonyloxy” or “alkylaminocarbonyloxygroup” mean a monovalent radical of the formula R₂NC(O)O—, where each Ris independently hydrogen or lower alkyl.

[0226] The term “alkoxycarbonylamino” or “alkoxycarbonylamino group”mean a monovalent radical of the formula ROC(O)NH—, where R is loweralkyl.

[0227] The terms “alkylcarbonylamino” or “alkylcarbonylamino group” or“alkanoylamino” or “alkanoylamino groups” mean a monovalent radical ofthe formula AlkC(O)NH—, where Alk is alkyl. Exemplary alkylcarbonylaminogroups include acetamido (CH₃C(O)NH—).

[0228] The terms “alkylaminocarbonyloxy” or “alkylaminocarbonyloxygroup” mean a monovalent radical of the formula AlkNHC(O)O—, where Alkis alkyl.

[0229] The terms “amino” or “amino group” mean an —NH₂ group.

[0230] The terms “alkylamino” or “alkylamino group” mean a monovalentradical of the formula (Alk)NH—, where Alk is alkyl. Exemplaryalkylamino groups include methylamino, ethylamino, propylamino,butylamino, tert-butylamino, and the like.

[0231] The terms “dialkylamino” or “dialkylamino group” mean amonovalent radical of the formula (Alk)(Alk)N—, where each Alk isindependently alkyl. Exemplary dialkylamino groups includedimethylamino, methylethylamino, diethylamino, dipropylamino,ethylpropylamino, and the like.

[0232] The terms “substituted amino” or “substituted amino group” mean amonovalent radical of the formula —NR₂, where each R is independently asubstituent selected from hydrogen or the specified substituents (butwhere both Rs cannot be hydrogen). Exemplary substituents include alkyl,alkanoyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heteroaryl,heteroarylalkyl, and the like.

[0233] The terms “alkoxycarbonylamino” or “alkoxycarbonylamino group”mean a monovalent radical of the formula AlkOC(O)NH—, where Alk isalkyl.

[0234] The terms “ureido” or “ureido group” mean a monovalent radical ofthe formula R₂NC(O)NH—, where each R is independently hydrogen or alkyl.

[0235] The terms “halogen” or “halogen group” mean a fluoro, chloro,bromo, or iodo group.

[0236] The term “halo” means one or more hydrogen atoms of the group arereplaced by halogen groups.

[0237] The terms “haloalkyl” or “haloalkyl group” mean a branched orstraight-chain saturated aliphatic hydrocarbon monovalent radical,wherein one or more hydrogen atoms thereof are each independentlyreplaced with halogen atoms. This term is exemplified by groups such aschloromethyl, 1,2-dibromoethyl, 1,1,1-trifluoropropyl, 2-iodobutyl,1-chloro-2-bromo-3-fluoropentyl, and the like.

[0238] The terms “sulfanyl”, “sulfanyl group”, “thioether”, or“thioether group” mean a divalent radical of the formula —S—.

[0239] The terms “alkylthio” or “alkylthio group” mean a monovalentradical of the formula AlkS—, where Alk is alkyl. Exemplary groupsinclude methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio,and the like.

[0240] The terms “sulfonyl” or “sulfonyl group” mean a divalent radicalof the formula —SO₂—.

[0241] The terms “sulfonylamino” or “sulfonylamino group” mean adivalent radical of the formula —SO₂NR—, where R is a hydrogen or asubstituent group.

[0242] The terms “aminosulfonyl” or “aminosulfonyl group” mean amonovalent radical of the formula NR₂SO₂—, where R is each independentlya hydrogen or a substituent group.

[0243] The terms “carbocycle”, “carbocyclyl”, “carbocyclic group” or“carbocyclyl group” mean a stable aliphatic 3- to 15-membered monocyclicor polycyclic monovalent or divalent radical consisting solely of carbonand hydrogen atoms which may comprise one or more fused or bridgedring(s), preferably a 5- to 7-membered monocyclic or 7- to 10-memberedbicyclic ring. Unless otherwise specified, the carbocycle may beattached at any carbon atom which results in a stable structure and, ifsubstituted, may be substituted at any suitable carbon atom whichresults in a stable structure. The term comprises cycloalkyl (includingspiro cycloalkyl), cycloalkylene, cycloalkenyl, cycloalkenylene,cycloalkynyl, and cycloalkynylene, and the like.

[0244] The terms “cycloalkyl” or “cycloalkyl group” mean a stablealiphatic saturated 3- to 15-membered monocyclic or polycyclicmonovalent radical consisting solely of carbon and hydrogen atoms whichmay comprise one or more fused or bridged ring(s), preferably a 5- to7-membered monocyclic or 7- to 10-membered bicyclic ring. Unlessotherwise specified, the cycloalkyl ring may be attached at any carbonatom which results in a stable structure and, if substituted, may besubstituted at any suitable carbon atom which results in a stablestructure. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl, norbornanyl, adamantyl, tetrahydronaphthyl (tetralin),1-decalinyl, bicyclo[2.2.2]octanyl, 1-methylcyclopropyl,2-methylcyclopentyl, 2-methylcyclooctyl, and the like.

[0245] The terms “cycloalkenyl” or “cycloalkenyl group” mean a stablealiphatic 3- to 15-membered monocyclic or polycyclic monovalent radicalhaving at least one carbon-carbon double bond and consisting solely ofcarbon and hydrogen atoms which may comprise one or more fused orbridged ring(s), preferably a 5- to 7-membered monocyclic or 7- to10-membered bicyclic ring. Unless otherwise specified, the cycloalkenylring may be attached at any carbon atom which results in a stablestructure and, if substituted, may be substituted at any suitable carbonatom which results in a stable structure. Exemplary cycloalkenyl groupsinclude cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl,cyclononenyl, cyclodecenyl, norbornenyl, 2-methylcyclopentenyl,2-methylcyclooctenyl, and the like.

[0246] The terms “cycloalkynyl” or “cycloalkynyl group” mean a stablealiphatic 8- to 15-membered monocyclic or polycyclic monovalent radicalhaving at least one carbon-carbon triple bond and consisting solely ofcarbon and hydrogen atoms which may comprise one or more fused orbridged ring(s), preferably a 8- to 10-membered monocyclic or 12- to15-membered bicyclic ring. Unless otherwise specified, the cycloalkynylring may be attached at any carbon atom which results in a stablestructure and, if substituted, may be substituted at any suitable carbonatom which results in a stable structure. Exemplary cycloalkynyl groupsinclude, cyclooctynyl, cyclononynyl, cyclodecynyl, 2-methylcyclooctynyl,and the like.

[0247] The terms “cycloalkylene” or “cycloalkylene group” mean a stablesaturated aliphatic 3- to 15-membered monocyclic or polycyclic divalentradical consisting solely of carbon and hydrogen atoms which maycomprise one or more fused or bridged ring(s), preferably a 5- to7-membered monocyclic or 7- to 10-membered bicyclic ring. Unlessotherwise specified, the cycloalkyl ring may be attached at any carbonatom which results in a stable structure and, if substituted, may besubstituted at any suitable carbon atom which results in a stablestructure. Exemplary cycloalkylene groups include cyclopentylene, andthe like.

[0248] The terms “cycloalkenylene” or “cycloalkenylene group” mean astable aliphatic 5- to 15-membered monocyclic or polycyclic divalentradical having at least one carbon-carbon double bond and consistingsolely of carbon and hydrogen atoms which may comprise one or more fusedor bridged ring(s), preferably a 5- to 7-membered monocyclic or 7- to10-membered bicyclic ring. Unless otherwise specified, thecycloalkenylene ring may be attached at any carbon atom which results ina stable structure and, if substituted, may be substituted at anysuitable carbon atom which results in a stable structure. Exemplarycycloalkenylene groups include cyclopentenylene, cyclohexenylene,cycloheptenylene, cyclooctenylene, cyclononenylene, cyclodecenylene,norbornenylene, 2-methylcyclopentenylene, 2-methylcyclooctenylene, andthe like.

[0249] The terms “cycloalkynylene” or “cycloalkynylene group” mean astable aliphatic 8- to 15-membered monocyclic or polycyclic divalentradical having at least one carbon-carbon triple bond and consistingsolely of carbon and hydrogen atoms which may comprise one or more fusedor bridged ring(s), preferably a 8- to 10-membered monocyclic or 12- to15-membered bicyclic ring. Unless otherwise specified, thecycloalkynylene ring may be attached at any carbon atom which results ina stable structure and, if substituted, may be substituted at anysuitable carbon atom which results in a stable structure. Exemplarycycloalkynylene groups include cyclooctynylene, cyclononynylene,cyclodecynylene, 2-methylcyclooctynylene, and the like.

[0250] The terms “aryl” or “aryl group” mean an aromatic carbocyclicmonovalent or divalent radical of from 6 to 14 carbon atoms having asingle ring (e.g., phenyl or phenylene) or multiple condensed rings(e.g., naphthyl or anthranyl). Unless otherwise specified, the aryl ringmay be attached at any suitable carbon atom which results in a stablestructure and, if substituted, may be substituted at any suitable carbonatom which results in a stable structure. Exemplary aryl groups includephenyl, naphthyl, anthryl, phenanthryl, indanyl, indenyl, biphenyl, andthe like. It may be abbreviated “Ar”.

[0251] The terms “heteroaryl” or “heteroaryl group” mean a stablearomatic 5- to 14-membered, monocyclic or polycyclic monovalent ordivalent radical which may comprise one or more fused or bridgedring(s), preferably a 5- to 7-membered monocyclic or 7- to 10-memberedbicyclic radical, having from one to four heteroatoms in the ring(s)independently selected from nitrogen, oxygen, and sulfur, wherein anysulfur heteroatoms may optionally be oxidized and any nitrogenheteroatom may optionally be oxidized or be quaternized. Unlessotherwise specified, the heteroaryl ring may be attached at any suitableheteroatom or carbon atom which results in a stable structure and, ifsubstituted, may be substituted at any suitable heteroatom or carbonatom which results in a stable structure. Exemplary and preferredheteroaryls include furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazinyl, indolizinyl, azaindolizinyl, indolyl, azaindolyl,diazaindolyl, dihydroindolyl, dihydroazaindoyl, isoindolyl,azaisoindolyl, benzofuranyl, furanopyridinyl, furanopyrimidinyl,furanopyrazinyl, furanopyridazinyl, dihydrobenzofuranyl,dihydrofuranopyridinyl, dihydrofuranopyrimidinyl, benzodioxolanyl,benzothienyl, thienopyridinyl, thienopyrimidinyl, thienopyrazinyl,thienopyridazinyl, dihydrobenzothienyl, dihydrothienopyridinyl,dihydrothienopyrimidinyl, indazolyl, azaindazolyl, diazaindazolyl,benzimidazolyl, imidazopyridinyl, benzthiazolyl, thiazolopyridinyl,thiazolopyrimidinyl, benzoxazolyl, oxazolopyridinyl, oxazolopyrimidinyl,benzisoxazolyl, purinyl, chromanyl, azachromanyl, quinolizinyl,quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl, isoquinolinyl,dihydroisoquinolinyl, tetrahydroisoquinolinyl, cinnolinyl,azacinnolinyl, phthalazinyl, azaphthalazinyl, quinazolinyl,azaquinazolinyl, quinoxalinyl, azaquinoxalinyl, naphthyridinyl,dihydronaphthyridinyl, tetrahydronaphthyridinyl, pteridinyl, carbazolyl,acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl, and the like.

[0252] The terms “heterocycle”, “heterocycle group”, “heterocyclyl”, or“heterocyclyl group” mean a stable non-aromatic 5- to 14-memberedmonocyclic or polycyclic, monovalent or divalent, ring which maycomprise one or more fused or bridged ring(s), preferably a 5- to7-membered monocyclic or 7- to 10-membered bicyclic ring, having fromone to three heteroatoms in the ring(s) independently selected fromnitrogen, oxygen, and sulfur, wherein any sulfur heteroatoms mayoptionally be oxidized and any nitrogen heteroatom may optionally beoxidized or be quaternized. Unless otherwise specified, the heterocyclylring may be attached at any suitable heteroatom or carbon atom whichresults in a stable structure and, if substituted, may be substituted atany suitable heteroatom or carbon atom which results in a stablestructure. Exemplary and preferred heterocycles include pyrrolinyl,pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl,tetrahydrofuranyl, hexahydropyrimidinyl, hexahydropyridazinyl, and thelike.

[0253] The term “compounds of Formula (I)” and equivalent expressionsare mean to embrace either or both of compounds of Formula (IA) andcompounds of Formula (IB) as the context permits.

[0254] The term “compounds of the invention” and equivalent expressionsare meant to embrace compounds of Formula (I) as herein described,including the tautomers, the prodrugs, the salts, particularly thepharmaceutically acceptable salts, and the solvates and hydratesthereof, where the context so permits. In general and preferably, thecompounds of the invention and the formulas designating the compounds ofthe invention are understood to only include the stable compoundsthereof and exclude unstable compounds, even if an unstable compoundmight be considered to be literally embraced by the compound formula.Similarly, reference to intermediates, whether or not they themselvesare claimed, is meant to embrace their salts and solvates, where thecontext so permits. For the sake of clarity, particular instances whenthe context so permits are sometimes indicated in the text, but theseinstances are purely illustrative and it is not intended to excludeother instances when the context so permits.

[0255] Specific compounds of the invention may be depicted by bothchemical structure and by chemical name. In the event that there may bea conflict between the chemical structure and chemical name set forth,it is understood that the chemical structure will control.

[0256] The terms “optional” or “optionally” mean that the subsequentlydescribed event or circumstances may or may not occur, and that thedescription includes instances where the event or circumstance occursand instances in which it does not. For example, “optionally substitutedaryl” means that the aryl radical may or may not be substituted and thatthe description includes both substituted aryl radicals and arylradicals having no substitution.

[0257] The terms “stable compound” or “stable structure” mean a compoundthat is sufficiently robust to survive isolation to a useful degree ofpurity from a reaction mixture, and formulation into an efficacioustherapeutic or diagnostic agent. For example, a compound which wouldhave a “dangling valency” or is a carbanion is not a compoundcontemplated by the invention.

[0258] The term “substituted” means that any one or more hydrogens on anatom of a group or moiety, whether specifically designated or not, isreplaced with a selection from the indicated group of substituents,provided that the atom's normal valency is not exceeded and that thesubstitution results in a stable compound. If a bond to a substituent isshown to cross the bond connecting two atoms in a ring, then suchsubstituent may be bonded to any atom on the ring. When a substituent islisted without indicating the atom via which such substituent is bondedto the rest of the compound, then such substituent may be bonded via anyatom in such substituent. For example, when the substituent ispiperazinyl, piperidinyl, or tetrazolyl, unless specified otherwise,such piperazinyl, piperidinyl, or tetrazolyl group may be bonded to therest of the compound of the invention via any atom in such piperazinyl,piperidinyl, or tetrazolyl group. Generally, when any substituent orgroup occurs more than one time in any constituent or compound, itsdefinition on each occurrence is independent of its definition at everyother occurrence. Thus, for example, if a group is shown to besubstituted with 0 to 2 R⁵, then such group is optionally substitutedwith up to two R⁵ groups and R⁵ at each occurrence is selectedindependently from the defined list of possible R⁵. Such combinations ofsubstituents and/or variables, however, are permissible only if suchcombinations result in stable compounds.

[0259] In a specific embodiment, the term “about” or “approximately”means within 20%, preferably within 10%, and more preferably within 5%of a given value or range.

[0260] The yield of each of the reactions described herein is expressedas a percentage of the theoretical yield.

[0261] B. Salt, Prodrug, Derivative, and Solvate Terms and Conventions

[0262] The terms “prodrug” or “prodrug derivative” mean acovalently-bonded derivative or carrier of the parent compound or activedrug substance which undergoes at least some biotransformation prior toexhibiting its pharmacological effect(s). In general, such prodrugs havemetabolically cleavable groups and are rapidly transformed in vivo toyield the parent compound, for example, by hydrolysis in blood, andgenerally include esters and amide analogs of the parent compounds. Theprodrug is formulated with the objectives of improved chemicalstability, improved patient acceptance and compliance, improvedbioavailability, prolonged duration of action, improved organselectivity, improved formulation (e.g., increased hydrosolubility),and/or decreased side effects (e.g., toxicity). In general, prodrugsthemselves have weak or no biological activity and are stable underordinary conditions. Prodrugs can be readily prepared from the parentcompounds using methods known in the art, such as those described in ATextbook of Drug Design and Development, Krogsgaard-Larsen and H.Bundgaard (eds.), Gordon & Breach, 1991, particularly Chapter 5: “Designand Applications of Prodrugs”; Design of Prodrugs, H. Bundgaard (ed.),Elsevier, 1985; Prodrugs: Topical and Ocular Drug Delivery, K. B. Sloan(ed.), Marcel Dekker, 1998; Methods in Enzymology, K. Widder et al.(eds.), Vol. 42, Academic Press, 1985, particularly pp. 309-396;Burger's Medicinal Chemistry and Drug Discovery, 5th Ed., M. Wolff(ed.), John Wiley & Sons, 1995, particularly Vol. 1 and pp. 172-178 andpp. 949-982; Pro-Drugs as Novel Delivery Systems, T. Higuchi and V.Stella (eds.), Am. Chem. Soc., 1975; and Bioreversible Carriers in DrugDesign, E. B. Roche (ed.), Elsevier, 1987, each of which is incorporatedherein by reference in their entireties.

[0263] The term “pharmaceutically acceptable prodrug” as used hereinmeans a prodrug of a compound of the invention which is, within thescope of sound medical judgment, suitable for use in contact with thetissues of humans and lower animals without undue toxicity, irritation,allergic response, and the like, commensurate with a reasonablebenefit/risk ratio, and effective for their intended use, as well as thezwitterionic forms, where possible.

[0264] The term “salt” means an ionic form of the parent compound or theproduct of the reaction between the parent compound with a suitable acidor base to make the acid salt or base salt of the parent compound. Saltsof the compounds of the present invention can be synthesized from theparent compounds which contain a basic or acidic moiety by conventionalchemical methods. Generally, the salts are prepared by reacting the freebase or acid parent compound with stoichiometric amounts or with anexcess of the desired salt-forming inorganic or organic acid or base ina suitable solvent or various combinations of solvents.

[0265] The term “pharmaceutically acceptable salt” means a salt of acompound of the invention which is, within the scope of sound medicaljudgment, suitable for use in contact with the tissues of humans andlower animals without undue toxicity, irritation, allergic response, andthe like, commensurate with a reasonable benefit/risk ratio, generallywater or oil-soluble or dispersible, and effective for their intendeduse. The term includes pharmaceutically-acceptable acid addition saltsand pharmaceutically-acceptable base addition salts. As the compounds ofthe present invention are useful in both free base and salt form, inpractice, the use of the salt form amounts to use of the base form.Lists of suitable salts are found in, e.g., S. M. Birge et al., J.Pharm. Sci., 1977, 66, pp. 1-19, which is hereby incorporated byreference in its entirety.

[0266] The term “pharmaceutically-acceptable acid addition salt” meansthose salts which retain the biological effectiveness and properties ofthe free bases and which are not biologically or otherwise undesirable,formed with inorganic acids such as hydrochloric acid, hydrobromic acid,hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoricacid, and the like, and organic acids such as acetic acid,trichloroacetic acid, trifluoroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,2-acetoxybenzoic acid, butyric acid, camphoric acid, camphorsulfonicacid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid,glutamic acid, glycolic acid, glycerophosphoric acid, hemisulfic acid,heptanoic acid, hexanoic acid, formic acid, fumaric acid,2-hydroxyethanesulfonic acid (isethionic acid), lactic acid, maleicacid, hydroxymaleic acid, malic acid, malonic acid, mandelic acid,mesitylenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid,nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, pamoic acid,pectinic acid, phenylacetic acid, 3-phenylpropionic acid, picric acid,pivalic acid, propionic acid, pyruvic acid, pyruvic acid, salicylicacid, stearic acid, succinic acid, sulfanilic acid, tartaric acid,p-toluenesulfonic acid, undecanoic acid, and the like.

[0267] The term “pharmaceutically-acceptable base addition salt” meansthose salts which retain the biological effectiveness and properties ofthe free acids and which are not biologically or otherwise undesirable,formed with inorganic bases such as ammonia or hydroxide, carbonate, orbicarbonate of ammonium or a metal cation such as sodium, potassium,lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum,and the like. Particularly preferred are the ammonium, potassium,sodium, calcium, and magnesium salts. Salts derived frompharmaceutically-acceptable organic nontoxic bases include salts ofprimary, secondary, and tertiary amines, quaternary amine compounds,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion-exchange resins, such as methylamine,dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine,isopropylamine, tripropylamine, tributylamine, ethanolamine,diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol,dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine,choline, betaine, ethylenediamine, glucosamine, methylglucamine,theobromine, purines, piperazine, piperidine, N-ethylpiperidine,tetramethylammonium compounds, tetraethylammonium compounds, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, N,N′-dibenzylethylenediamine, polyamine resins, and thelike. Particularly preferred organic nontoxic bases are isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline,and caffeine.

[0268] The term “solvate” means a physical association of a compoundwith one or more solvent molecules or a complex of variablestoichiometry formed by a solute (for example, a compound of Formula(I)) and a solvent, for example, water, ethanol, or acetic acid. Thisphysical association may involve varying degrees of ionic and covalentbonding, including hydrogen bonding. In certain instances, the solvatewill be capable of isolation, for example, when one or more solventmolecules are incorporated in the crystal lattice of the crystallinesolid. In general, the solvents selected do not interfere with thebiological activity of the solute. Solvates encompasses bothsolution-phase and isolatable solvates. Representative solvates includehydrates, ethanolates, methanolates, and the like.

[0269] The term “hydrate” means a solvate wherein the solventmolecule(s) is/are H₂O.

[0270] The compounds of the present invention as discussed below includethe free base or acid thereof, their salts, solvates, and prodrugs andmay include oxidized sulfur atoms or quaternized nitrogen atoms in theirstructure, although not explicitly stated or shown, particularly thepharmaceutically acceptable forms thereof. Such forms, particularly thepharmaceutically acceptable forms, are intended to be embraced by theappended claims.

[0271] C. Isomer Terms and Conventions

[0272] The term “isomers” means compounds having the same number andkind of atoms, and hence the same molecular weight, but differing withrespect to the arrangement or configuration of their atoms in space. Theterm includes stereoisomers and geometric isomers.

[0273] The terms “stereoisomer” or “optical isomer” means a stableisomer that has at least one chiral atom or restricted rotation givingrise to perpendicular dissymmetric planes (e.g., certain biphenyls,allenes, and spiro compounds) and can rotate plane-polarized light.Because asymmetric centers and other chemical structure exist in thecompounds of the invention which may give rise to stereoisomerism, theinvention contemplates stereoisomers and mixtures thereof. The compoundsof the invention and their salts include asymmetric carbon atoms and maytherefore exist as single stereoisomers, racemates, and as mixtures ofenantiomers and diastereomers. Typically, such compounds will beprepared as a racemic mixture. If desired, however, such compounds canbe prepared or isolated as pure stereoisomers, i.e., as individualenantiomers or diastereomers, or as stereoisomer-enriched mixtures. Asdiscussed in more detail below, individual stereoisomers of compoundsare prepared by synthesis from optically active starting materialscontaining the desired chiral centers or by preparation of mixtures ofenantiomeric products followed by separation or resolution, such asconversion to a mixture of diastereomers followed by separation orrecrystallization, chromatographic techniques, use of chiral resolvingagents, or direct separation of the enantiomers on chiralchromatographic columns. Starting compounds of particularstereochemistry are either commercially available or are made by themethods described below and resolved by techniques well-known in theart.

[0274] The term “enantiomers” means a pair of stereoisomers that arenon-superimposable mirror images of each other.

[0275] The terms “diastercoisomers” or “diastereomers” meanstereoisomers which are not mirror images of each other.

[0276] The terms “racemic mixture” or “racemate” mean a mixturecontaining equal parts of individual enantiomers.

[0277] The term “non-racemic mixture” means a mixture containing unequalparts of individual enantiomers.

[0278] The term “geometrical isomer” means a stable isomer which resultsfrom restricted freedom of rotation about double bonds (e.g.,cis-2-butene and trans-2-butene) or in a cyclic structure (e.g.,cis-1,3-dichlorocyclobutane and trans-1,3-dichlorocyclobutane). Becausecarbon-carbon double (olefinic) bonds, C═N double bonds, cyclicstructures, and the like may be present in the compounds of theinvention, the invention contemplates each of the various stablegeometric isomers and mixtures thereof resulting from the arrangement ofsubstituents around these double bonds and in these cyclic structures.The substituents and the isomers are designated using the cis/transconvention or using the E or Z system, wherein the term “E” means higherorder substituents on opposite sides of the double bond, and the term“Z” means higher order substituents on the same side of the double bond.A thorough discussion of E and Z isomerism is provided in J. March,Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4thed., John Wiley & Sons, 1992, which is hereby incorporated by referencein its entirety. Several of the following examples represent single Eisomers, single Z isomers, and mixtures of E/Z isomers. Determination ofthe E and Z isomers can be done by analytical methods such as x-raycrystallography, ¹H NMR, and ¹³C NMR.

[0279] Some of the compounds of the invention can exist in more than onetautomeric form. As mentioned above, the compounds of the inventioninclude all such tautomers.

[0280] It is well-known in the art that the biological andpharmacological activity of a compound is sensitive to thestereochemistry of the compound. Thus, for example, enantiomers oftenexhibit strikingly different biological activity including differencesin pharmacokinetic properties, including metabolism, protein binding,and the like, and pharmacological properties, including the type ofactivity displayed, the degree of activity, toxicity, and the like.Thus, one skilled in the art will appreciate that one enantiomer may bemore active or may exhibit beneficial effects when enriched relative tothe other enantiomer or when separated from the other enantiomer.Additionally, one skilled in the art would know how to separate, enrich,or selectively prepare the enantiomers of the compounds of the inventionfrom this disclosure and the knowledge in the art.

[0281] Thus, although the racemic form of drug may be used, it is oftenless effective than administering an equal amount of enantiomericallypure drug; indeed, in some cases, one enantiomer may bepharmacologically inactive and would merely serve as a simple diluent.For example, although ibuprofen had been previously administered as aracemate, it has been shown that only the S-isomer of ibuprofen iseffective as an anti-inflammatory agent (in the case of ibuprofen,however, although the R-isomer is inactive, it is converted in vivo tothe S-isomer, thus, the rapidity of action of the racemic form of thedrug is less than that of the pure S-isomer). Furthermore, thepharmacological activities of enantiomers may have distinct biologicalactivity. For example, S-penicillamine is a therapeutic agent forchronic arthritis, while R-penicillamine is toxic.

[0282] Indeed, some purified enantiomers have advantages over theracemates, as it has been reported that purified individual isomers havefaster transdermal penetration rates compared to the racemic mixture.See U.S. Pat. Nos. 5,114,946 and 4,818,541.

[0283] Thus, if one enantiomer is pharmacologically more active, lesstoxic, or has a preferred disposition in the body than the otherenantiomer, it would be therapeutically more beneficial to administerthat enantiomer preferentially. In this way, the patient undergoingtreatment would be exposed to a lower total dose of the drug and to alower dose of an enantiomer that is possibly toxic or an inhibitor ofthe other enantiomer.

[0284] Preparation of pure enantiomers or mixtures of desiredenantiomeric excess (ee) or enantiomeric purity are accomplished by oneor more of the many methods of (a) separation or resolution ofenantiomers, or (b) enantioselective synthesis known to those of skillin the art, or a combination thereof. These resolution methods generallyrely on chiral recognition and include, for example, chromatographyusing chiral stationary phases, enantioselective host-guestcomplexation, resolution or synthesis using chiral auxiliaries,enantioselective synthesis, enzymatic and nonenzymatic kineticresolution, or spontaneous enantioselective crystallization. Suchmethods are disclosed generally in Chiral Separation Techniques: APractical Approach (2nd Ed.), G. Subramanian (ed.), Wiley-VCH, 2000; T.E. Beesley and R. P. W. Scott, Chiral Chromatography, John Wiley & Sons,1999; and Satinder Ahuja, Chiral Separations by Chromatography, Am.Chem. Soc., 2000. Furthermore, there are equally well-known methods forthe quantitation of enantiomeric excess or purity, for example, GC,HPLC, CE, or NMR, and assignment of absolute configuration andconformation, for example, CD ORD, X-ray crystallography, or NMR.

[0285] In general, all tautomeric forms and isomeric forms and mixtures,whether individual geometric isomers or stereoisomers or racemic ornon-racemic mixtures, of a chemical structure or compound is intended,unless the specific stereochemistry or isomeric form is specificallyindicated in the compound name or structure.

[0286] D. Pharmaceutical Administration and Diagnostic and TreatmentTerms and Conventions

[0287] The term “patient” includes both human and non-human mammals.

[0288] The term “effective amount” means an amount of a compoundaccording to the invention which, in the context of which it isadministered or used, is sufficient to achieve the desired effect orresult. Depending on the context, the term effective amount may includeor be synonymous with a pharmaceutically effective amount or adiagnostically effective amount.

[0289] The terms “pharmaceutically effective amount” or “therapeuticallyeffective amount” means an amount of a compound according to theinvention which, when administered to a patient in need thereof, issufficient to effect treatment for disease-states, conditions, ordisorders for which the compounds have utility. Such an amount would besufficient to elicit the biological or medical response of a tissue,system, or patient that is sought by a researcher or clinician. Theamount of a compound of according to the invention which constitutes atherapeutically effective amount will vary depending on such factors asthe compound and its biological activity, the composition used foradministration, the time of administration, the route of administration,the rate of excretion of the compound, the duration of treatment, thetype of disease-state or disorder being treated and its severity, drugsused in combination with or coincidentally with the compounds of theinvention, and the age, body weight, general health, sex, and diet ofthe patient. Such a therapeutically effective amount can be determinedroutinely by one of ordinary skill in the art having regard to their ownknowledge, the prior art, and this disclosure.

[0290] The term “diagnostically effective amount” means an amount of acompound according to the invention which, when used in a diagnosticmethod, apparatus, or assay, is sufficient to achieve the desireddiagnostic effect or the desired biological activity necessary for thediagnostic method, apparatus, or assay. Such an amount would besufficient to elicit the biological or medical response in a diagnosticmethod, apparatus, or assay, which may include a biological or medicalresponse in a patient or in a in vitro or in vivo tissue or system, thatis sought by a researcher or clinician. The amount of a compoundaccording to the invention which constitutes a diagnostically effectiveamount will vary depending on such factors as the compound and itsbiological activity, the diagnostic method, apparatus, or assay used,the composition used for administration, the time of administration, theroute of administration, the rate of excretion of the compound, theduration of administration, drugs and other compounds used incombination with or coincidentally with the compounds of the invention,and, if a patient is the subject of the diagnostic administration, theage, body weight, general health, sex, and diet of the patient. Such adiagnostically effective amount can be determined routinely by one ofordinary skill in the art having regard to their own knowledge, theprior art, and this disclosure.

[0291] The term “modulate” means the ability of a compound to alter thefunction of the glucocorticoid receptor by, for example, binding to andstimulating or inhibiting the glucocorticoid receptor functionalresponses.

[0292] The term “modulator” in the context of describing compoundsaccording to the invention means a compound that modulates theglucocorticoid receptor function. As such, modulators include, but arenot limited to, agonists, partial agonists, antagonists, and partialantagonists.

[0293] The term “agonist” in the context of describing compoundsaccording to the invention means a compound that, when bound to theglucocorticoid receptor, enhances or increases the glucocorticoidreceptor function. As such, agonists include partial agonists and fullagonists.

[0294] The term “full agonist” in the context of describing compoundsaccording to the invention means a compound that evokes the maximalstimulatory response from the glucocorticoid receptor, even when thereare spare (unoccupied) glucocorticoid receptors present.

[0295] The term “partial agonist” in the context of describing compoundsaccording to the invention means a compound that is unable to evoke themaximal stimulatory response from the glucocorticoid receptor, even atconcentrations sufficient to saturate the glucocorticoid receptorspresent.

[0296] The term “antagonist” in the context of describing compoundsaccording to the invention means a compound that directly or indirectlyinhibits or suppresses the glucocorticoid receptor function. As such,antagonists include partial antagonists and full antagonists.

[0297] The term “full antagonist” in the context of describing compoundsaccording to the invention means a compound that evokes the maximalinhibitory response from the glucocorticoid receptor, even when thereare spare (unoccupied) glucocorticoid receptors present.

[0298] The term “partial antagonist” in the context of describingcompounds according to the invention means a compound that is unable toevoke the maximal inhibitory response from the glucocorticoid receptor,even at concentrations sufficient to saturate the glucocorticoidreceptors present.

[0299] The terms “treating” or “treatment” mean the treatment of adisease-state in a patient, and include:

[0300] (i) preventing the disease-state from occurring in a patient, inparticular, when such patient is genetically or otherwise predisposed tothe disease-state but has not yet been diagnosed as having it;

[0301] (ii) inhibiting or ameliorating the disease-state in a patient,e.g., arresting or slowing its development, or inhibiting orameliorating a symptom of the disease state; or

[0302] (iii) relieving the disease-state in a patient, i.e., causingregression or cure of the disease-state.

[0303] General Synthetic Methods

[0304] The invention also provides processes for making compounds ofFormulas (IA) and (IB). In the schemes below directed to the synthesisof Formula (IA) compounds, unless specified otherwise, R¹ to R⁷ in theformulas shall have the meaning of R¹ to R⁷ in the Formula (IA) of theinvention described hereinabove. Likewise, in the schemes below directedto the synthesis of Formula (IB) compounds, unless specified otherwise,R¹ to R⁸ in the formulas shall have the meaning of R¹ to R⁸ in theFormula (IB) of the invention described hereinabove. Intermediates usedin the preparation of compounds of the invention are either commerciallyavailable or readily prepared by methods known to those skilled in theart. Additional methods for preparing particular intermediates are alsoto be found in U.S. Provisional Application No. 60/367,801 filed Mar.26, 2002, (Y. Bekkali, et al; Attny. Docket No. 9/239 PV) and in U.S.Provisional Application No. 60/367,758 filed Mar. 26, 2002, (Y. Bekkali,et al; Attny Docket No. 9/240 PV), both of which applications are hereinincorporated by reference.

[0305] Optimum reaction conditions and reaction times may vary dependingon the particular reactants used. Unless otherwise specified, solvents,temperatures, pressures, and other reaction conditions may be readilyselected by one of ordinary skill in the art. Specific procedures areprovided in the Synthetic Examples section. Typically, reaction progressmay be monitored by thin layer chromatography (TLC), if desired, andintermediates and products may be purified by chromatography on silicagel and/or by recrystallization.

[0306] Compounds of Formula (IA) wherein R⁶ and R⁷ are both hydrogen maybe prepared by the method outlined in Scheme I (Method A):

[0307] As illustrated in Scheme I (Method A), an ester intermediate ofFormula (II) where R′ is Me or Et, is reduced with a suitable reducingagent, such as lithium aluminum hydride, in a suitable solvent, such asTHF or diethyl ether, to produce the 1,2-diol of Formula (III).Oxidative cleavage of 1,2-diols is well known in the art and may beachieved with periodic acid or lead tetraacetate, for example, in asuitable solvent, such as methanol, to provide the ketone (IV).Conversion of ketone (IV) to a sulfinic acid amide, such as at-butylsulfinic acid amide, may be accomplished by reaction with asuitable Lewis acid, preferably Ti(OEt)₄, and an alkylsulfinamide of theformula RS(O)NH₂ (wherein R is alkyl), preferably t-butylsulfinamide, toproduce V. Reaction of V with a suitable organometallic reagent R⁵R⁴M,such as a Grignard reagent (M is MgBr, MgCl or MgI) or an organolithiumreagent (M is Li), in a suitable solvent such as THF or diethyl ether,provides the desired compound of Formula (IA) upon hydrolysis. Suchorganolithium reagents and alkylmagnesium halides or Grignard reagentsare well known in the art. For example, Grignard reagents are easilyprepared by the reaction of the corresponding alkyl halide withmagnesium metal in a suitable solvent, such as ether or THF, underanhydrous conditions.

[0308] Intermediates of Formula (II) may be prepared by methods known inthe art. Two procedures are illustrated in Scheme II (Methods B and C):

[0309] For an R¹ group which will undergo a Friedel-Crafts alkylation(Method B), one may react a pyruvate (VI) bearing CF₃ and where R′ is Meor Et, with a bromomethyl olefin (VII) bearing an R² and an olefin group(═CH—R″) that will become R³, in the presence of manganese and a Lewisacid such as zinc chloride in a suitable solvent such as THF to producea 2-hydroxy ester (VIII). Friedel-Crafts alkylation of R¹ with thisintermediate (VIII) in the presence of a suitable Lewis acid such asaluminum chloride provides (II) (R³=—CH₂R″). Alternatively (Method C)one may perform a Grignard reaction with a pyruvate bearing CF₃ (VI) andan ethyl magnesium halide (IX) bearing R¹, R², and R³ to provide thedesired intermediate (II).

[0310] Compounds of Formula (IA) wherein R⁶ and R⁷ are both hydrogen mayalso be prepared by the method outlined in Scheme III (Method D):

[0311] In this approach, trifluoroacetic anhydride (X) andN,O-dimethylhydroxylamine hydrochloride (XI) are coupled under basicconditions, e.g., in the presence of a suitable base, to affordtrifluoroacetamide (XII) (Weinreb amide). The Weinreb amide (XII) isreacted with a vinyl magnesium bromide bearing R² and R³ in a suitablesolvent to afford the trifluoromethylenone intermediate (XIII). Thistrifluoromethylenone intermediate is treated with an organocopperreagent R¹Cu (not shown), derived ill-situ from a Grignard ororganolithium reagent R¹—M (where M is Li or MgX where X is halogen) bytreating with a copper salt CuX (where X is halogen), in a suitablesolvent to afford the 1,4-addition product IV. Intermediate IV is thenconverted to (IA) as described in Scheme I.

[0312] Compounds of Formula (IB) wherein R⁶ and R⁷ are both hydrogen maybe prepared by the procedure illustrated in Scheme IV (Method E):

[0313] In this method, a substituted phenol (XIV) is reacted with anacryloyl chloride bearing R² and R³ (XV) in the presence of a suitablebase such as triethylamine to provide an intermediate ester (not shown)which is cyclized in-situ by treatment with a Lewis acid, such asaluminum trichloride, in a suitable solvent such as carbon disulfide toprovide lactone (XVI). The lactone is treated with a suitable amineHNR″R′″, such as morpholine, such that in the resulting amide (XVII),—NR″R′″ will function as a leaving group in the subsequent reaction. Theintermediate phenol that forms (not shown) is protected, for example, byreaction in-situ with an alkyl halide RX (where R is alkyl and X ishalogen), such as methyl iodide, in the presence of a suitable base suchas potassium hydroxide to form the protected phenol in which theprotecting group is an alkoxy group as shown in (XVII). The amide (XVII)is then reacted with an organometallic reagent (R⁸M), such as a Grignardreagent (M is MgBr or MgCl) or an organolithium reagent (M is Li), in asuitable solvent such as THF or diethyl ether to provide ketone (XVIII).Conversion of (XVIII) to a sulfinic acid amide using suitableconditions, for example as described in the second-to-last step inScheme I, provides (XIX) (where R is alkyl). Reaction of (XIX) withR⁵R⁴M as described in the last step in Scheme I provides the desiredcompound of Formula (IB) where R¹ is an optionally substitutedalkoxyphenyl group.

[0314] In a more general procedure to prepare the formula (IB) compoundswherein R⁶ and R⁷ are both hydrogen, suitable for a variety of R¹groups, one may use a method analogous to that described in Scheme III.As illustrated in Scheme V (Method F) below, using a Weinreb amidebearing R⁸ (XXI) one may employ the method described in Scheme III toprepare the desired compound of Formula (IB).

[0315] Conventional techniques known to those skilled in the art can beused to prepare the substituted-amino compounds of Formulas (IA) and(IB), i.e. wherein R⁶ and/or R⁷ are other than hydrogen, from thecorresponding unsubstituted-amino compounds wherein R⁶ and/or R⁷ areboth hydrogen described above. For example, the unsubstituted-aminocompounds of Formulas (IA) and (IB) may be N-alkylated usingconventional techniques to prepare the corresponding N-alkylatedcompounds. In this approach, the nitrogen of compounds of Formula (IA)and (IB) undergoes reductive amination with aldehydes in suitablesolvents, such as acetonitrile or 1,2-dichloroethane, and in thepresence of suitable reducing agents, such as sodium cyanoborohydride orsodium triacetoxyborohydride, to give the corresponding tri- ordi-substituted amine compound, respectively. In another example, theunsubstituted-amino compounds of Formula (IA) and (IB) may be N-acylatedusing conventional techniques to prepare the corresponding N-acylatedcompounds. In this method, compounds of Formula (IA) and (IB) undergoacylation with desired acid anhydrides upon heating in a suitablesolvent, such as 1,2-dichloroethane, to give the correspondingN-mono-acylated product. Other known techniques may be used to prepareother substituted-amino derivatives of the compounds of Formulae (IA)and (IB) from the corresponding unsubstituted-amino compounds.

[0316] In order that this invention be more fully understood, thefollowing examples are set forth. These examples are for the purpose ofillustrating embodiments of this invention, and are not to be construedas limiting the scope of the invention in any way.

[0317] The examples which follow are illustrative and, as recognized byone skilled in the art, particular reagents or conditions could bemodified as needed for individual compounds. Starting materials used inthe scheme below are either commercially available or easily preparedfrom commercially available materials by those skilled in the art.

SYNTHETIC EXAMPLES Example 1 Synthesis of 2-methylpropane-2-sulfinicacid[3-(5-fluoro-2-methoxyphenyl)-3-methyl-1-trifluoromethylbut-(Z)-ylidene]-amide(Methods A and B)

[0318]

[0319] To a mixture of 8.5 g (49.9 mmol) of ethyltrifluoromethylpyruvate, 6.6 g (120 mmol) of manganese, and 0.65 g (4.8mmol) of zinc chloride in 40 mL of THF warmed at reflux, was added 200microL (2 mmol) of 1-bromo-2-methylpropene. After 30 min, 9.13 mL (90.5mmol) of 1-bromo-2-methylpropene in 30 mL of THF was added dropwise overa 1 hour period. The mixture was refluxed for 1 hour after the addition,and was then cooled to 0° C. and diluted with 150 mL of saturatedaqueous ammonium chloride and 100 mL of EtOAc. The organic phase wasseparated and the aqueous layer extracted with three 100 mL portions ofEtOAc. The combined organic layers were washed with two 50 mL portionsof saturated aqueous ammonium chloride, two 50 mL portions of brine,dried over magnesium sulfate (MgSO₄), filtered, and concentrated invacuo. The crude residue was purified by silica gel chromatographyeluting with EtOAc-hexane (5:95) to afford 5.9 g (52%) of2-hydroxy-4-methyl-2-trifluoromethylpent-4-enoic acid ethyl ester.

[0320] To a mixture of 5.9 g (26.1 mmol) of the above2-hydroxy-4-methyl-2-trifluoromethylpent-4-enoic acid ethyl ester in 30mL of 4-fluoroanisole was added 5.2 g (39.4 mmol) of aluminum chloridein several portions. The mixture became exothermic and turned black withthe first addition and was cooled with an ice-water bath. The mixturewas stirred for 3 days and was then poured into 200 mL of ice-cold 1 Naqueous HCl and extracted with three 150 mL portions of EtOAc. Thecombined organic layers were washed with 50 mL of 1 N aqueoushydrochloric acid, three 50 mL portions of brine, dried over magnesiumsulfate, filtered, and concentrated in vacuo. The crude residue waspurified by silica gel chromatography eluting with EtOAc-hexane (1:9,then 2:8, then 3:7, then 4:6) to afford 6.6 g (71%) of4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentanoicacid ethyl ester.

[0321] To a chilled solution (ice-water bath) of 6 g (17.0 mmol) of theabove4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentanoicacid ethyl ester in 60 mL of dry THF, 2.4 g (61.5 mmol) of lithiumaluminum hydride was added in portions. After the addition, the coldbath was removed and the mixture was stirred at room temperatureovernight. The mixture was then warmed at reflux for 3 hours and thencautiously quenched by slow addition to 100 mL of THF containing 2 mL ofwater. Additional water was then cautiously added for a total of 15 mLand the resulting mixture stirred for 2 hours. The excess water wasdried with magnesium sulfate and 300 mL of EtOAc was added. After 1hour, the mixture was filtered through diatomaceous earth andconcentrated in vacuo to afford 4.9 g (92%) of4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethylpentane-1,2-diolas an oil.

[0322] To a solution of 4.9 g (15.8 mmol) of the above4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethylpentane-1,2-diolin 100 mL of MeOH was added 10 g (45.9 mmol) of sodium periodate. Themixture was stirred for 4 hours and was then diluted with 100 mL ofether and 100 mL of hexane, filtered through diatomaceous earth, andconcentrated in vacuo. The crude residue was dissolved in hexane andpassed through a pad of silica gel, eluting first with hexane then withEtOAc-hexane (2:98, then 4:96) to afford 3.85 g (87%) of1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one as aclear oil.

[0323] To a mixture of 500 mg (1.8 mmol) of1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one and0.86 mL (3.6 mmol) of a solution of Ti(OEt)₄ in EtOH (˜20% Ti) in 7 mLof THF was added 240 mg (2 mmol) t-butylsulfinamide. The reaction waswarmed at reflux for 6 h and then cooled to room temperature, dilutedwith 1 mL of brine and EtOAc and filtered through diatomaceous earth andconcentrated to afford an oil. The residue was absorbed onto silica geland chromatographed on silica gel eluting with hexanes-EtOAc (98:2) toafford 300 mg (44%) of 2-methylpropane-2-sulfinic acid[3-(5-fluoro-2-methoxyphenyl)-3-methyl-1-trifluoromethylbut-(Z)-ylidene]-amideas an orange oil.

[0324] Additional examples showing the preparation of particularintermediates useful in the synthetic methods of the present inventionare shown in Examples 2 and 3 below:

Example 2 Synthesis of2-hydroxy-4-methyl-4-phenyl-2-trifluoromethylpentanoic acid ethyl ester(Method C)

[0325]

[0326] To a room temperature solution of 45 mL (22.5 mmol) of a 0.5 Msolution of 2-methyl-2-phenylpropylmagnesium chloride in diethyl etherwas added 38 g (22.5 mmol) of ethyl trifluoropyruvate in 10 mL ofanhydrous THF. The reaction became slightly warm to the touch and awhite precipitate quickly developed. After 2 hours, the reaction wasdiluted with diethyl ether and quenched with 1 N aqueous HCl. Theaqueous layer was separated and extracted with ether. The combinedorganic layers were dried over magnesium sulfate, filtered, andconcentrated in vacuo to afford a brown oil. Chromatography on silicagel eluting with hexanes-EtOAc (98:2), afforded the title compound as aclear, colorless oil (4.6 g, 67%).

[0327] This intermediate may then be used as described in Example 1 andScheme I of the General Synthetic Methods section to produce compoundsof the invention.

Example 3 Synthesis of1,1,1-trifluoro-4-(4-fluorophenyl)-4-methylpentan-2-one (Method D)

[0328]

[0329] To a mixture of 15.8 g of N,O-dimethylhydroxylamine hydrochlorideand 21.7 mL of trifluoroacetic anhydride in 400 mL of CH₂Cl₂ was added37 mL of pyridine dropwise at 0° C. The resulting mixture was allowed tostir at 0° C. for 30 min and then quenched with water. The organic layerwas washed with water, 1 N HCl, water, and brine, dried over magnesiumsulfate, filtered, and concentrated in vacuo. The residual colorless oilwas placed under vacuum for 5 min, providing2,2,2-trifluoro-N-methoxy-N-methylacetamide which was used for the nextreaction without further purification.

[0330] A mixture of 3 g of the above2,2,2-trifluoro-N-methoxy-N-methylacetamide in 30 mL of anhydrous etherwas cooled to 0° C. and treated with 42 mL of 0.5 M solution of2-methylpropenylmagnesium bromide in THF. The reaction mixture wasstirred at 0° C. for 30 min and then allowed to warm to roomtemperature. The resulting mixture was stirred at room temperatureovernight. The reaction was quenched with saturated aqueous ammoniumchloride (NH₄Cl) and extracted with ether three times. The organiclayers were combined and washed with water and brine, dried overmagnesium sulfate, and filtered. The resulting ether/THF solution of1,1,1-trifluoro-4-methylpent-3-en-2-one was used for the next reactionwithout further purification.

[0331] To a 2 M ether/THF solution of the above1,1,1-trifluoro-4-methylpent-3-en-2-one was added 3.8 g of CuI and 10 mLof 2 M ether solution of 4-fluorophenylmagnesium bromide at 0° C. Themixture was warmed to room temperature and stirred for 2 hours. Thereaction was quenched with saturated aqueous ammonium chloride andextracted with EtOAc three times. The combined organic layers werewashed with water, brine, dried over magnesium sulfate, filtered, andconcentrated in vacuo. The residue was purified by flash chromatographyto yield 460 mg of the title compound.

[0332] This intermediate may then be used as described in Example 1 andScheme III of the General Synthetic Methods section to produce compoundsof the invention.

Example 43-(5-Fluoro-2-methoxy-phenyl)-3-methyl-1-(pyridin-2-ylmethyl)-1-trifluoromethyl-butylamine(Compound 1)

[0333]

[0334] To a chilled (−78 C.) solution of 0.05 mL (0.514 mmol) of2-methylpyridine in 3 mL of dry THF was added 0.23 mL (0.4 mmol) of a1.7 M solution of t-BuLi in pentane. The mixture turned a bright orange.After 10 min, a solution of 98 mg (0.257 mmol) of2-methyl-propane-2-sulfinic acid[3-(5-fluoro-2-methoxy-phenyl)-3-methyl-1-trifluoromethyl-but-(Z)-ylidene]-amidein 0.5 mL of anhydrous THF was added. The reaction was then warmed toroom temperature, quenched with aqueous ammonium chloride, stirred for30 min and extracted with diethyl ether.(3×) The combined organic layerswere dried (MgSO₄), filtered and concentrated. The residue was dissolvedin 2 mL of methanol, 3 drops of concentrated HCl were added and thereaction was warmed at 75° C. in a sealed tube. After 1 h, the reactionwas cooled to room temperature, concentrated in vacuo, neutralized withaqueous sodium bicarbonate and extracted with EtOAc (3×). The combinedorganic layers were dried over (MgSO₄), filtered and concentrated toafford an oil. The residue was purified by preparative thin layerchromatography eluting with hexanes-EtOAc (95:5) to afford 24 mg (25%)of the title compound.

Example 5 Synthesis of3-(5-Fluoro-2-methoxy-phenyl)-1-(1H-indol-2-ylmethyl)-3-methyl-1-trifluoromethyl-butylamine(Compound 2)

[0335]

[0336] To a chilled (−78 C.) solution of 40 mg (0.30 mmol) of2-methylindole in 3 mL of diethyl ether was added 0.56 mL (0.91 mmol) ofa 1.6 M solution of n-BuLi in hexanes. The resulting orange solution wasstirred for 5 min and treated with 0.60 mL (0.60 mmol) of a solution of1 M solution of KOt-Bu in THF. The reaction was slowly warmed until abright yellow precipitate formed. After 5 min, the reaction mixture wascooled to −78° C. and treated with 138 mg (0.362 mmol) of a solution of2-methyl-propane-2-sulfinic acid[3-(5-fluoro-2-methoxy-phenyl)-3-methyl-1-trifluoromethyl-but-(Z)-ylidene]-amidein 0.5 mL of diethyl ether. Next, the mixture was warmed to roomtemperature, quenched with aqueous ammonium chloride and extracted withEtOAc (3×). The combined organic layers were dried over (MgSO₄),filtered and concentrated. The residue was dissolved in 2 mL ofmethanol, 3 drops of concentrated HCl were added and the reaction warmedat 75° C. in a sealed tube. After 1 h, the reaction was cooled to roomtemperature, concentrated in vacuo, neutralized with aqueous sodiumbicarbonate and extracted with EtOAc (3×). The combined organic layerswere dried (MgSO₄), filtered and concentrated to leave an oil. Theresidue was purified by preparative thin layer chromatography elutingwith toluene to afford an oil that had to be further purified bypreparative thin layer chromatography eluting with hexanes-EtOAc (9:1)to afford 40 mg (33%) of the title compound.

Example 6 Synthesis of3-(5-Fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butylamine(Compound 12)

[0337]

[0338] A solution of Lepidine (588 μL, 4.5 mmol) in THF (3 mL) wastreated with LDA (1.5 M in cyclohexane, 3.0 mL) at −50° C. under N₂atmosphere. The reaction mixture was stirred at −50° C. for 30 min ,cooled to −78° C., treated with a solution of 2-methylpropane-2-sulfinicacid[3-(5-fluoro-2-methoxyphenyl)-3-methyl-1-trifluoromethylbut(Z)-ylidine]-amide(565 mg, 1.5 mmol) in THF (4 mL) and stirred for 4 h. The mixture wasquenched with water (8 mL) and diluted with EtOAc (20 mL). Phases wereseparated and the aqueous layer was extracted with EtOAc (5×5 mL). Thecombined organic layers were dried over MgSO₄, filtered, concentratedand purified on SiO₂ (60%-80% EtOAc:Hexanes). The product was dissolvedin MeOH (4 mL), treated with HCl (4M in Dioxane, 4 eq.) and stirred for4 h. The reaction was concentrated to an oil, redissolved in CHCl₃ (20mL) and quenched with NaHCO₃ (sat. 20 mL). Phases were separated and theaqueous layer was extracted with CHCl₃ (4×10 mL). Organic layers werepooled, dried over MgSO₄, filtered and concentrated in vacuo. Theresidue was purified on SiO₂ (40% -60%, EtOAc/Hexane) to give 599.0 mg(96%) of the title product as an oil.

Example 7 Synthesis of[3-(5-Fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butyl]-methyl-amine(Compound 24)

[0339]

[0340] A solution of3-(5-fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butylamine(42.0 mg, 0.1 mmol) and formaldehyde (8 μL, 0.1 mmol) in dichloroethane(2 mL) was stirred for 30 min at room temperature in the presence of 4Amolecular sieves (200 mg). The reaction mixture was acidified withacetic acid (57 μL, 1.0 mmol), stirred for 16 h and treated with sodiumtriacetoxy borohydride (42.4 mg, 0.2 mmol). The resulting mixture wasstirred at room temperature for 3 h and quenched with NaHCO₃ (sat. 6mL). Phases were separated and the aqueous layer was extracted withCHCl₃ (2×4 mL). The combined organic layers were dried over MgSO₄,filtered and concentrated in vacuo. The residue was purified on SiO₂(20%-40%, EtOAc:Hexanes) to give 24.0 mg (55%) of the title compound.

Example 8 Synthesis ofN-[3-(5-Fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butyl]-acetamide(Compound 30)

[0341]

[0342] A solution of3-(5-fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butylamine(42.0 mg, 0.1 mmol) in dichloroethane (4 mL) was treated with aceticanhydride (71 μL, 1.0 mmol). The mixture was stirred for 16 h at 85° C.and quenched with NaHCO₃ (sat, 4 mL). Phases were separated and theaqueous layer was extracted with CHCl₃ (3×2 mL). The combined organiclayers were dried over MgSO₄, filtered and concentrated in vacuo. Theresidue was purified on SiO₂ (50%-70%, EtOAc:hexanes) to give 34.0 mg(74%) of the title product.

Example 9 Synthesis of[3-(5-Fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butyl]-dimethyl-amine(Compound 29)

[0343]

[0344] A solution of3-(5-Fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butylamine(42.0 mg, 0.1 mmol) and the formaldehyde (1.49 ml, 20 mmol) inacetonitrile (2 ml) was stirred for 30 minutes at room temperature. Thereaction mixture was acidified with acetic acid (57 μL, 1.0 mmol) andtreated with sodium cyanoborohydride (31.4 mg, 0.5 mmol). The resultingmixture was stirred at room temperature for 15 h and quenched withNaHCO₃ (sat. 2 ml). Phases were separated and the aqueous layer wasextracted with CHCl₃ (3×2ml). The combined organic layers were driedover MgSO₄, filtered and concentrated in vacuo. The resulting oil wasdissolved in Et₂O and treated with HCl (2M in Ether) until the mixturewas acidic (pH˜2). The ether layer was decanted and the salt was washedwith ether (5×2 ml) and dried. The solid was dissolved in CHCl₃,extracted with NaHCO₃ (sat.), phases were separated and the aqueouslayer was extracted with CHCl₃ (2×4 ml). The combined organic layerswere dried over MgSO₄, filtered and concentrated. The residue waspurified on SiO₂ (20%-30%, EtOAc: Hexanes) to give 12.5 mg (28%) of thetitle compound.

[0345] Compounds nos. 3 to 11, 13 to 23, 25 to 29 and 31 to 48, setforth in the tables above, may be made by the procedures described inthe General Synthetic Methods section and Examples 1-9.

[0346] Assessment of Biological Properties

[0347] Compounds of the invention were evaluated for binding to thesteroid receptor by a fluorescence polarization competitive bindingassay. Detailed descriptions for preparation of recombinantglucocorticoid receptor (GR) complex used in the assay is described inGoldrick et al., U.S. provisional application No. 60/291,877, filed May18, 2001 (corresponding to Goldrick et al., U.S. nonprovisionalapplication No. 10/151,133, filed May 20, 2002, Attny. Docket No. 9/205)both incorporated herein by reference in their entirety. Preparation ofthe tetramethyl rhodamine (TAMRA)-labeled dexamethasone probe wasaccomplished using a standard literature procedure (M. Pons et al., J.Steroid Biochem., 1985, 22, pp. 267-273).

[0348] A. Glucocorticoid Receptor Competitive Binding Assay

[0349] Step 1. Characterization of the Fluorescent Probe

[0350] The wavelengths for maximum excitation and emission of thefluorescent probe should first be measured. An example of such a probeis rhodamine (TAMRA)-labeled dexamethasone.

[0351] The affinity of the probe for the steroid receptor was thendetermined in a titration experiment. The fluorescence polarizationvalue of the probe in assay buffer was measured on an SLM-8100fluorometer using the excitation and emission maximum values describedabove. Aliquots of expression vector lysate were added and fluorescencepolarization was measured after each addition until no further change inpolarization value was observed. Non-linear least squares regressionanalysis was used to calculate the dissociation constant of the probefrom the polarization values obtained for lysate binding to the probe.

[0352] Step 2. Screening for Inhibitors of Probe Binding

[0353] This assay uses fluorescence polarization (FP) to quantitate theability of test compounds to compete with tetramethyl rhodamine(TAMRA)-labeled dexamethasone for binding to a human glucocorticoidreceptor (GR) complex prepared from an insect expression system. Theassay buffer was: 10 mM TES, 50 mM KCl, 20 mM Na₂MoO₄.2H₂O, 1.5 mM EDTA,0.04% w/v CHAPS, 10% v/v glycerol, 1 mM dithiothreitol, pH 7.4. Testcompounds were dissolved to 1 mM in neat DMSO and then further dilutedto 10× assay concentration in assay buffer supplemented with 10% v/vDMSO. Test compounds were serially diluted at 10× assay concentrationsin 10% DMSO-containing buffer in 96-well polypropylene plates. Bindingreaction mixtures were prepared in 96-well black Dynex microtiter platesby sequential addition of the following assay components to each well:15 μL of 10× test compound solution, 85 μL of GR-containing baculoviruslysate diluted 1:170 in assay buffer, and 50 μL of 15 nM TAMRA-labeleddexamethasone. Positive controls were reaction mixtures containing notest compound; negative controls (blanks) were reaction mixturescontaining 0.7 μM to 2 μM dexamethasone. The binding reactions wereincubated for 1 hour at room temperature and then read for fluorescencepolarization in the LJL Analyst set to 550 nm excitation and 580 nmemission, with the Rhodamine 561 dichroic mirror installed. IC₅₀ valueswere determined by iterative non-linear curve fitting of the FP signaldata to a 4-parameter logistic equation.

[0354] Compounds found to bind to the glucocorticoid receptor may beevaluated for binding to the progesterone receptor (PR), estrogenreceptor (ER), and mineralocorticoid receptors to evaluate thecompound's selectivity for GR. The protocols for PR and MR are identicalto the above GR method, with the following exceptions: PR insect celllysate is diluted 1:7.1 and MR lysate diluted 1:9.4. PR probe isTAMRA-labeled mifepristone, used at a final concentration of 5 nM in theassay, and the negative controls (blanks) were reactions containingmifepristone at 0.7 μM to 2 μM.

[0355] The ER protocol is similar to the above protocols, but usesPanVera kit receptor, fluorescein-labeled probe. The assay componentsare made in the same volumes as above, to produce final assayconcentrations for ER of 15 nM and ES2 probe of 1 nM. In addition, thecomponent order of addition is modified from the above assays: probe isadded to the plate first, followed by receptor and test compound. Theplates are read in the LJL Analyst set to 485 nm excitation and 530 nmemission, with the Fluorescein 505 dichroic mirror installed.

[0356] Compounds found to bind to the glucocorticoid receptor may beevaluated for dissociation of transactivation and transrepression byassays cited in the Background of the Invention (C. M. Bamberger and H.M. Schulte, Eur. J. Clin. Invest., 2000, 30 (suppl. 3) 6-9) or by theassays described below.

[0357] B. Glucocorticoid Receptor Cell Assays

[0358] 1. Induction of Aromatase in Fibroblasts (Cell Assay forTransactivation)

[0359] Dexamethasone, a synthetic ligand to the glucocorticoid receptor(GR), induces expression of aromatase in human foreskin fibroblastcells. The activity of aromatase is measured by the conversion oftestosterone to estradiol in culture media. Compounds that exhibitbinding to GR are evaluated for their ability to induce aromataseactivity in human foreskin fibroblasts.

[0360] Human foreskin fibroblast cells (ATCC Cat. No. CRL-2429,designation CCD 112SK) are plated on 96 well plates at 50,000 cells perwell 5 days before use, in Iscove's Modified Dulbecco's Media (GibcoBRLLife Technologies Cat No. 12440-053) supplemented with 10% charcoalfiltered FBS (Clonetech Cat No. SH30068) and Gentamycin (GibcoBRL LifeTechnologies Cat. No. 15710-064). On the day of the experiment, themedia in the wells is replaced with fresh media. Cells are treated withtest compounds to final concentrations of 10⁻⁵ M to 10⁻⁸ M, andtestosterone to a final concentration of 300 ng/mL. Each well has atotal volume of 100 μL. Samples are made in duplicates. Control wellsinclude: (a) wells that receive testosterone only, and) wells thatreceive testosterone plus 2 μM of dexamethasone to provide maximuminduction of aromatase. Plates are incubated at 37° C. overnight (15 to18 hours), and supernatants are harvested at the end of incubation.Estradiol in the supernatant is measured using ELISA kits for estradiol(made by ALPCO, obtained from American Laboratory Products Cat. No.020-DR-2693) according to the manufacture's instruction. The amount ofestradiol is inversely proportional to the ELISA signals in each well.The extent of aromatase induction by test compounds is expressed as arelative percentage to dexamethasone. EC₅₀ values of test compounds arederived by non-linear curve fitting.

[0361] 2. Inhibition of IL-6 Production in Fibroblasts (Cell Assay forTransrepression)

[0362] Human foreskin fibroblast cells produce IL-6 in response tostimulation by pro-inflammatory cytokine IL-1. This inflammatoryresponse, as measured by the production of IL-6, can be effectivelyinhibited by dexamethasone, a synthetic ligand to the glucocorticoidreceptor (GR). Compounds that exhibit binding to GR are evaluated fortheir ability to inhibit IL-6 production in human foreskin fibroblasts.

[0363] Human foreskin fibroblast cells (ATCC Cat. No. CRL-2429) areplated on 96 well plates at 5,000 cells per well the day before use, inIscove's Modified Dulbecco's Media (GibcoBRL Life Technologies Cat. No.12440-053) supplemented with 10% charcoal filtered FBS (Clonetech Cat.No. SH30068) and Gentamycin (GibcoBRL Life Technologies Cat. No.15710-064). On the next day, media in the wells is replaced with freshmedia. Cells are treated with IL-1 (rhIL-1α, R&D Systems Cat. No.200-LA) to a final concentration of 1 ng/mL, and with test compounds tofinal concentrations of 10⁻⁵ M to 10⁻⁸ M, in a total volume of 200 μLper well. Samples are done in duplicates. Background control wells donot receive test compounds or IL-1. Positive control wells receive IL-1only and represent maximum (or 100%) amount of IL-6 production. Platesare incubated at 37° C. overnight (15 to 18 hours), and supernatants areharvested at the end of incubation. IL-6 levels in the supernatants aredetermined by the ELISA kits for IL-6 (MedSystems Diagnostics GmbH,Vienna, Austria, Cat. No. BMS213TEN) according to manufacture'sinstructions. The extent of inhibition of IL-6 by test compounds isexpressed in percentage relative to positive controls. IC₅₀ values oftest compounds are derived by non-linear curve fitting.

[0364] Evaluation of agonist or antagonist activity of compounds bindingto the glucocorticoid receptor may be determined by any of the assays.

[0365] 3. Modulation of Tyrosine Aminotransferase (TAT) Induction in RatHepatoma Cells

[0366] Testing of compounds for agonist or antagonist activity ininduction of tyrosine aminotransferase (TAT) in rat hepatoma cells.

[0367] H4-II-E-C3 cells were incubated overnight in 96 well plates(20,000 cells/100 μL/well) in MEM medium containing 10% heat inactivatedFBS and 1% nonessential amino acids. On the next day, cells werestimulated with the indicated concentrations of dexamethasone or testcompound (dissolved in DMSO, final DMSO concentration 0.2%) for 18hours. Control cells were treated with 0.2% DMSO. After 18 hours, thecells were lysed in a buffer containing 0.1% Triton X-100 and the TATactivity was measured in a photometric assay using tyrosine andalpha-ketoglutarate as substrates.

[0368] For measuring antagonist activity, the hepatoma cells werepre-stimulated by addition of dexamethasone (concentration ranges from3×10⁻⁹ M to 3×10⁻⁸ M) shortly before the test compound was applied tothe cells. The steroidal non-selective GR/PR antagonist mifepristone wasused as control.

[0369] 4. Modulation of MMTV-Luc Induction in HeLa Cells

[0370] Testing of compounds for agonist or antagonist activity instimulation of MMTV-(mouse mammary tumor virus) promoter in HeLa cells.

[0371] HeLa cells were stably co-transfected with the pHHLuc-plasmidcontaining a fragment of the MMTV-LTR (−200 to +100 relative to thetranscription start site) cloned in front of the luciferase gene(Norden, 1988) and the pcDNA3.1 plasmid (Invitrogen) constitutivelyexpressing the resistance for the selective antibiotic GENETICIN®.Clones with best induction of the MMTV-promoter were selected and usedfor further experiments.

[0372] Cells were cultured overnight in DMEM medium without phenol red,supplemented with 3% CCS (charcoal treated calf serum) and thentransferred to 96 well plates (15,000 cells/100 μL/well). On the nextday, activation of the MMTV-promoter was stimulated by addition of testcompound or dexamethasone dissolved in DMSO (final concentration 0.2%).Control cells were treated with DMSO only. After 18 hours, the cellswere lysed with cell lysis reagent (Promega, Cat. No. E1531), luciferaseassay reagent (Promega, Cat. No. E1501) was added and the glowluminescence was measured using a luminometer (BMG, Offenburg).

[0373] For measuring antagonist activity, the MMTV-promoter waspre-stimulated by adding dexamethasone (3×10⁻⁹ M to 3×10⁻⁸ M) shortlybefore the test compound was applied to the cells. The steroidalnon-selective GR/PR antagonist mifepristone was used as control.

[0374] 5. Modulation of IL-8 Production in U937 Cells

[0375] Testing of compounds for agonist or antagonist activity inGR-mediated inhibition of LPS-induced IL-8 secretion in U-937 cells.

[0376] U-937 cells were incubated for 2 to 4 days in RPMI1640 mediumcontaining 10% CCS (charcoal treated calf serum). The cells weretransferred to 96 well plates (40,000 cells/100 μL/well) and stimulatedwith 1 μg/mL LPS (dissolved in PBS) in the presence or absence ofdexamethasone or test compound (dissolved in DMSO, final concentration0.2%). Control cells were treated with 0.2% DMSO. After 18 hours, theIL-8 concentration in the cell supernatant was measured by ELISA, usingthe “OptEIA human IL-8 set” (Pharmingen, Cat. No. 2654KI).

[0377] For measuring antagonist activity, the LPS-induced IL-8 secretionwas inhibited by adding dexamethasone (3×10⁻⁹ M to 3×10⁻⁸ M) shortlybefore the test compound was applied to the cells. The steroidalnon-selective GR/PR antagonist mifepristone was used as control.

[0378] 6. Modulation of ICAM-Luc Expression in HeLa Cells

[0379] Testing of compounds for agonist or antagonist activity ininhibition of TNF-alpha-induced activation of the ICAM-promoter in HeLacells.

[0380] HeLa cells were stably co-transfected with a plasmid containing a1.3 kb fragment of the human ICAM-promoter (−1353 to −9 relative to thetranscription start site, Ledebur and Parks, 1995) cloned in front ofthe luciferase gene and the pcDNA3.1 plasmid (Invitrogen) whichconstitutively expresses the resistance for the antibiotic GENETICIN®.Clones with best induction of the ICAM-promoter were selected and usedfor further experiments. Cells were transferred to 96 well plates(15,000 cells/100 μL/well) in DMEM medium supplemented with 3% CCS. Onthe following day the activation of the ICAM-promoter was induced byaddition of 10 ng/mL recombinant TNF-alpha (R&D System, Cat. No.210-TA). Simultaneously the cells were treated with the test compound ordexamethasone (dissolved in DMSO, final concentration 0.2%). Controlcells were treated with DMSO only. After 18 hours, the cells were lysedwith cell lysis reagent (Promega, Cat. No. E1531), luciferase assayreagent (Promega, Cat. No. E1501) was added and glow luminescence wasmeasured using a luminometer (BMG, Offenburg).

[0381] For measuring antagonist activity, the TNF-alpha-inducedactivation of the ICAM-promoter was inhibited by adding dexamethasone(3×10⁻⁹ M to 3×10⁻⁸ M) shortly before the test compound was applied tothe cells. The steroidal non-selective GR/PR antagonist mifepristone wasused as control.

[0382] In general, the preferred potency range in the above assays isbetween 0.1 nM and 10 μM, the more preferred potency range is 0.1 nM to1 μM, and the most preferred potency range is 0.1 nM to 100 nM.

[0383] Representative compounds of the invention have been tested andhave shown activity as modulators of the glucocorticoid receptorfunction in one or more of the above assays. For example, the followingcompounds of Formula (IA) have demonstrated activity in the GR bindingassay:

[0384]3-(5-Fluoro-2-methoxy-phenyl)-1-(1H-indol-2-ylmethyl)-3-methyl-1-trifluoromethyl-butylamine;

[0385]3-(5-Fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butylamine;

[0386][3-(5-Fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butyl]-isobutyl-amine;

[0387][3-(5-Fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butyl]-propyl-amine;

[0388]Butyl-[3-(5-fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butyl]-amine;and

[0389][3-(5-Fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butyl]-methyl-amine.

[0390] The invention also provides methods of modulating theglucocorticoid receptor function in a patient comprising administeringto the patient a compound according to the invention. If the purpose ofmodulating the glucocorticoid receptor function in a patient is to treata disease-state or condition, the administration preferably comprises atherapeutically or pharmaceutically effective amount of apharmaceutically acceptable compound according to the invention. If thepurpose of modulating the glucocorticoid receptor function in a patientis for a diagnostic or other purpose (e.g., to determine the patient'ssuitability for therapy or sensitivity to various sub-therapeutic dosesof the compounds according to the invention), the administrationpreferably comprises an effective amount of a compound according to theinvention, that is, the amount necessary to obtain the desired effect ordegree of modulation.

[0391] Methods of Therapeutic Use

[0392] As pointed out above, the compounds of the invention are usefulin modulating the glucocorticoid receptor function. In doing so, thesecompounds have therapeutic use in treating disease-states and conditionsmediated by the glucocorticoid receptor function or that would benefitfrom modulation of the glucocorticoid receptor function.

[0393] As the compounds of the invention modulate the glucocorticoidreceptor function, they have very useful anti-inflammatory andantiallergic, immune-suppressive, and anti-proliferative activity andthey can be used in patients as drugs, particularly in the form ofpharmaceutical compositions as set forth below, for the treatment ofdisease-states and conditions.

[0394] The agonist compounds according to the invention can be used inpatients as drugs for the treatment of the following disease-states orindications that are accompanied by inflammatory, allergic, and/orproliferative processes:

[0395] (i) Lung diseases: chronic, obstructive lung diseases of anygenesis, particularly bronchial asthma and chronic obstructive pulmonarydisease (COPD); adult respiratory distress syndrome (ARDS);bronchiectasis; bronchitis of various genesis; all forms of restrictivelung diseases, particularly allergic alveolitis; all forms of lungedema, particularly toxic lung edema; all forms of interstitial lungdiseases of any genesis, e.g., radiation pneumonitis; and sarcoidosisand granulomatoses, particularly Boeck disease;

[0396] (ii) Rheumatic diseases or autoimmune diseases or joint diseases:all forms of rheumatic diseases, especially rheumatoid arthritis, acuterheumatic fever, and polymyalgia rheumatica; reactive arthritis;rheumatic soft tissue diseases; inflammatory soft tissue diseases ofother genesis; arthritic symptoms in degenerative joint diseases(arthroses); traumatic arthritis; collagenoses of any genesis, e.g.,systemic lupus erythematosus, scleroderma, polymyositis,dermatomyositis, Sjögren syndrome, Still disease, and Felty syndrome;

[0397] (iii) Allergic diseases: all forms of allergic reactions, e.g.,angioneurotic edema, hay fever, insect bites, allergic reactions todrugs, blood derivatives, contrast agents, etc., anaphylactic shock(anaphylaxis), urticaria, angioneurotic edema, and contact dermatitis;

[0398] (iv) Vasculitis diseases: panarteritis nodosa, polyarteritisnodosa, arteritis temporalis, Wegner granulomatosis, giant cellarthritis, and crythema nodosum;

[0399] (v) Dermatological diseases: atopic dermatitis, particularly inchildren; psoriasis; pityriasis rubra pilaris; erythematous diseasestriggered by various noxa, e.g., rays, chemicals, burns, etc.; bullousdermatoses; diseases of the lichenoid complex; pruritus (e.g., ofallergic genesis); seborrheic dermatitis; rosacea; pemphigus vulgaris;erythema multiforme exudativum; balanitis; vulvitis; hair loss, such asoccurs in alopecia areata; and cutaneous T cell lymphomas;

[0400] (vi) Renal diseases: nephrotic syndrome; and all types ofnephritis, e.g., glomerulonephritis;

[0401] (vii) Hepatic diseases: acute liver cell disintegration; acutehepatitis of various genesis, e.g., viral, toxic, drug-induced; andchronically aggressive and/or chronically intermittent hepatitis;

[0402] (viii) Gastrointestinal diseases: inflammatory bowel diseases,e.g., regional enteritis (Crohn disease), colitis ulcerosa; gastritis;peptic esophagitis (refluxoesophagitis); and gastroenteritis of othergenesis, e.g., nontropical sprue;

[0403] (ix) Proctological diseases: anal eczema; fissures; hemorrhoids;and idiopathic proctitis;

[0404] (x) Eye diseases: allergic keratitis, uveitis, or iritis;conjunctivitis; blepharitis; neuritis nervi optici; choroiditis; andsympathetic ophthalmia;

[0405] (xi) Diseases of the ear, nose, and throat (ENT) area: allergicrhinitis or hay fever; otitis externa, e.g., caused by contact eczema,infection, etc.; and otitis media;

[0406] (xii) Neurological diseases: brain edema, particularlytumor-related brain edema; multiple sclerosis; acute encephalomyelitis;meningitis; acute spinal cord injury; stroke; and various forms ofseizures, e.g., nodding spasms;

[0407] (xiii) Blood diseases: acquired hemolytic anemia; and idiopathicthrombocytopenia;

[0408] (xiv) Tumor diseases: acute lymphatic leukemia; malignantlymphoma; lymphogranulomatoses; lymphosarcoma; extensive metastases,particularly in mammary, bronchial, and prostatic carcinoma;

[0409] (xv) Endocrine diseases: endocrine ophthalmopathy; endocrineorbitopathia;

[0410] thyrotoxic crisis; Thyroiditis de Quervain; Hashimotothyroiditis; Morbus Basedow; granulomatous thyroiditis; strumalymphomatosa; and Grave disease;

[0411] (xvi) Organ and tissue transplantations and graft-versus-hostdiseases;

[0412] (xvii) Severe states of shock, e.g., septic shock, anaphylacticshock, and systemic inflammatory response syndrome (SIRS);

[0413] (xviii) Substitution therapy in: congenital primary adrenalinsufficiency, e.g., adrenogenital syndrome; acquired primary adrenalinsufficiency, e.g., Addison disease, autoimmune adrenalitis,post-infection, tumors, metastases, etc.;

[0414] congenital secondary adrenal insufficiency, e.g., congenitalhypopituitarism; and

[0415] acquired secondary adrenal insufficiency, e.g., post-infection,tumors, metastases, etc.;

[0416] (xix) Pain of inflammatory genesis, e.g., lumbago; and

[0417] (xx) various other disease-states or conditions including type Idiabetes (insulin-dependent diabetes), osteoarthritis, Guillain-Barresyndrome, restenosis following percutaneous transluminal coronaryangioplasty, Alzheimer disease, acute and chronic pain, atherosclerosis,reperfusion injury, bone resorption diseases, congestive heart failure,myocardial infarction, thermal injury, multiple organ injury secondaryto trauma, acute purulent meningitis, necrotizing enterocolitis andsyndromes associated with hemodialysis, leukopheresis, and granulocytetransfusion.

[0418] In addition, the compounds according to the invention can be usedfor the treatment of any other disease-states or conditions notmentioned above which have been treated, are treated, or will be treatedwith synthetic glucocorticoids (see, e.g., H. J. Hatz, Glucocorticoide:Immunologische Grundlagen Pharmakologie und Therapierichtlinien[Glucocorticoids: Immunological Fundamentals, Pharmacology, andTherapeutic Guidelines], Stuttgart: Verlagsgesellschaft mbH, 1998, whichis hereby incorporated by reference in its entirety). Most or all of theindications (i) through (xx) mentioned above are described in detail inH. J. Hatz, Glucocorticoide: Immunologische Grundlagen, Pharmakologieund Therapierichtlinien. Furthermore, the compounds of the invention canalso be used to treat disorders other than those listed above ormentioned or discussed herein, including in the Background of theInvention.

[0419] The antagonist compounds according to the invention, whether fullantagonists or partial antagonists, can be used in patients as drugs forthe treatment of the following disease-states or indications, withoutlimitation: type II diabetes (non-insulin-dependent diabetes); obesity;cardiovascular diseases; hypertension; arteriosclerosis; neurologicaldiseases, such as psychosis and depression; adrenal and pituitarytumors; glaucoma; and Cushing syndrome based on an ACTH-secreting tumorlike pituitary adenoma. In particular, the compounds of the inventionare useful for treating obesity and all disease-states and indicationsrelated to a deregulated fatty acids metabolism such as hypertension,atherosclerosis, and other cardiovascular diseases. Using the compoundsof the invention that are GR antagonists, it should be possible toantagonize both the carbohydrate metabolism and fatty acids metabolism.Thus, the antagonist compounds of the invention are useful in treatingall disease-states and conditions that involve increased carbohydrate,protein, and lipid metabolism and would include disease-states andconditions leading to catabolism like muscle frailty (as an example ofprotein metabolism).

[0420] Methods of Diagnostic Use

[0421] The compounds of the invention may also be used in diagnosticapplications and for commercial and other purposes as standards incompetitive binding assays. In such uses, the compounds of the inventionmay be used in the form of the compounds themselves or they may bemodified by attaching a radioisotope, luminescence, fluorescent label orthe like in order to obtain a radioisotope, luminescence, or fluorescentprobe, as would be known by one of skill in the art and as outlined inHandbook of Fluorescent Probes and Research Chemicals, 6th Edition, R.P. Haugland (ed.), Eugene: Molecular Probes, 1996; Fluorescence andLuminescence Probes for Biological Activity, W. T. Mason (ed.), SanDiego: Academic Press, 1993; Receptor-Ligand Interaction, A PracticalApproach, E. C. Hulme (ed.), Oxford: IRL Press, 1992, each of which ishereby incorporated by reference in their entireties.

[0422] General Administration and Pharmaceutical Compositions

[0423] When used as pharmaceuticals, the compounds of the invention aretypically administered in the form of a pharmaceutical composition. Suchcompositions can be prepared using procedures well known in thepharmaceutical art and comprise at least one compound of the invention.The compounds of the invention may also be administered alone or incombination with adjuvants that enhance stability of the compounds ofthe invention, facilitate administration of pharmaceutical compositionscontaining them in certain embodiments, provide increased dissolution ordispersion, increased inhibitory activity, provide adjunct therapy, andthe like. The compounds according to the invention may be used on theirown or in conjunction with other active substances according to theinvention, optionally also in conjunction with other pharmacologicallyactive substances. In general, the compounds of this invention areadministered in a therapeutically or pharmaceutically effective amount,but may be administered in lower amounts for diagnostic or otherpurposes.

[0424] In particular, the compounds of the invention are useful incombination with glucocorticoids or corticosteroids. As pointed outabove, standard therapy for a variety of immune and inflammatorydisorders includes administration of corticosteroids, which have theability to suppress immunologic and inflammatory responses. (A. P.Truhan et al., Annals of Allergy, 1989, 62, pp. 375-391; J. D. Baxter,Hospital Practice, 1992, 27, pp. 111-134; R. P. Kimberly, Curr. Opin.Rheumatol., 1992, 4, pp. 325-331; M. H. Weisman, Curr. Opin. Rheumatol.,1995, 7, pp. 183-190; W. Sterry, Arch. Dermatol. Res., 1992, 284(Suppl.), pp. S27-S29). While therapeutically beneficial, however, theuse of corticosteroids is associated with a number of side effects,ranging from mild to possibly life threatening, especially withprolonged and/or high dose steroid usage. Accordingly, methods andcompositions that enable the use of a lower effective dosage ofcorticosteroids (referred to as the “steroid sparing effect”) would behighly desirable to avoid unwanted side effects. The compounds of theinvention provide such a steroid sparing effect by achieving the desiredtherapeutic effect while allowing the use of lower doses and lessfrequent administration of glucocorticoids or corticosteroids.

[0425] Administration of the compounds of the invention, in pure form orin an appropriate pharmaceutical composition, can be carried out usingany of the accepted modes of administration of pharmaceuticalcompositions. Thus, administration can be, for example, orally, buccally(e.g., sublingually), nasally, parenterally, topically, transdermally,vaginally, or rectally, in the form of solid, semi-solid, lyophilizedpowder, or liquid dosage forms, such as, for example, tablets,suppositories, pills, soft elastic and hard gelatin capsules, powders,solutions, suspensions, or aerosols, or the like, preferably in unitdosage forms suitable for simple administration of precise dosages. Thepharmaceutical compositions will generally include a conventionalpharmaceutical carrier or excipient and a compound of the invention asthe/an active agent, and, in addition, may include other medicinalagents, pharmaceutical agents, carriers, adjuvants, diluents, vehicles,or combinations thereof. Such pharmaceutically acceptable excipients,carriers, or additives as well as methods of making pharmaceuticalcompositions for various modes or administration are well-known to thoseof skill in the art. The state of the art is evidenced, e.g., byRemington: The Science and Practice of Pharmacy, 20th Edition, A.Gennaro (ed.), Lippincott Williams & Wilkins, 2000; Handbook ofPharmaceutical Additives, Michael & Irene Ash (eds.), Gower, 1995;Handbook of Pharmaceutical Excipients, A. H. Kibbe (ed.), AmericanPharmaceutical Ass'n, 2000; H. C. Ansel and N. G. Popovish,Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea andFebiger, 1990; each of which is incorporated herein by reference intheir entireties to better describe the state of the art.

[0426] As one of skill in the art would expect, the forms of thecompounds of the invention utilized in a particular pharmaceuticalformulation will be selected (e.g., salts) that possess suitablephysical characteristics (e.g., water solubility) that is required forthe formulation to be efficacious.

[0427] Pharmaceutical compositions suitable for buccal (sub-lingual)administration include lozenges comprising a compound of the presentinvention in a flavored base, usually sucrose, and acacia or tragacanth,and pastilles comprising the compound in an inert base such as gelatinand glycerin or sucrose and acacia.

[0428] Pharmaceutical compositions suitable for parenteraladministration comprise sterile aqueous preparations of a compound ofthe present invention. These preparations are preferably administeredintravenously, although administration can also be effected by means ofsubcutaneous, intramuscular, or intradermal injection. Injectablepharmaceutical formulations are commonly based upon injectable sterilesaline, phosphate-buffered saline, oleaginous suspensions, or otherinjectable carriers known in the art and are generally rendered sterileand isotonic with the blood. The injectable pharmaceutical formulationsmay therefore be provided as a sterile injectable solution or suspensionin a nontoxic parenterally acceptable diluent or solvent, including1,3-butanediol, water, Ringer's solution, isotonic sodium chloridesolution, fixed oils such as synthetic mono- or diglycerides, fattyacids such as oleic acid, and the like. Such injectable pharmaceuticalformulations are formulated according to the known art using suitabledispersing or setting agents and suspending agents. Injectablecompositions will generally contain from 0.1 to 5% w/w of a compound ofthe invention.

[0429] Solid dosage forms for oral administration of the compoundsinclude capsules, tablets, pills, powders, and granules. For such oraladministration, a pharmaceutically acceptable composition containing acompound(s) of the invention is formed by the incorporation of any ofthe normally employed excipients, such as, for example, pharmaceuticalgrades of mannitol, lactose, starch, pregelatinized starch, magnesiumstearate, sodium saccharine, talcum, cellulose ether derivatives,glucose, gelatin, sucrose, citrate, propyl gallate, and the like. Suchsolid pharmaceutical formulations may include formulations, as are wellknown in the art, to provide prolonged or sustained delivery of the drugto the gastrointestinal tract by any number of mechanisms, whichinclude, but are not limited to, pH sensitive release from the dosageform based on the changing pH of the small intestine, slow erosion of atablet or capsule, retention in the stomach based on the physicalproperties of the formulation, bioadhesion of the dosage form to themucosal lining of the intestinal tract, or enzymatic release of theactive drug from the dosage form. Liquid dosage forms for oraladministration of the compounds include emulsions, microemulsions,solutions, suspensions, syrups, and elixirs, optionally containingpharmaceutical adjuvants in a carrier, such as, for example, water,saline, aqueous dextrose, glycerol, ethanol and the like. Thesecompositions can also contain additional adjuvants such as wetting,emulsifying, suspending, sweetening, flavoring, and perfuming agents.

[0430] Topical dosage forms of the compounds include ointments, pastes,creams, lotions, gels, powders, solutions, sprays, inhalants, eyeointments, eye or ear drops, impregnated dressings and aerosols, and maycontain appropriate conventional additives such as preservatives,solvents to assist drug penetration and emollients in ointments andcreams. Topical application may be once or more than once per daydepending upon the usual medical considerations. Furthermore, preferredcompounds for the present invention can be administered in intranasalform via topical use of suitable intranasal vehicles. The formulationsmay also contain compatible conventional carriers, such as cream orointment bases and ethanol or oleyl alcohol for lotions. Such carriersmay be present as from about 1% up to about 98% of the formulation, moreusually they will form up to about 80% of the formulation.

[0431] Transdermal administration is also possible. Pharmaceuticalcompositions suitable for transdermal administration can be presented asdiscrete patches adapted to remain in intimate contact with theepidermis of the recipient for a prolonged period of time. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen. Such patches suitably contain a compoundof the invention in an optionally buffered, aqueous solution, dissolvedand/or dispersed in an adhesive, or dispersed in a polymer. A suitableconcentration of the active compound is about 1% to 35%, preferablyabout 3% to 15%.

[0432] For administration by inhalation, the compounds of the inventionare conveniently delivered in the form of an aerosol spray from a pumpspray device not requiring a propellant gas or from a pressurized packor a nebulizer with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane, carbondioxide, or other suitable gas. In any case, the aerosol spray dosageunit may be determined by providing a valve to deliver a metered amountso that the resulting metered dose inhaler (MDI) is used to administerthe compounds of the invention in a reproducible and controlled way.Such inhaler, nebulizer, or atomizer devices are known in the art, forexample, in PCT International Publication Nos. WO 97/12687 (particularlyFIG. 6 thereof, which is the basis for the commercial RESPIMAT®nebulizer); WO 94/07607; WO 97/12683; and WO 97/20590, to whichreference is hereby made and each of which is incorporated herein byreference in their entireties.

[0433] Rectal administration can be effected utilizing unit dosesuppositories in which the compound is admixed with low-meltingwater-soluble or insoluble solids such as fats, cocoa butter,glycerinated gelatin, hydrogenated vegetable oils, mixtures ofpolyethylene glycols of various molecular weights, or fatty acid estersof polyethylene glycols, or the like. The active compound is usually aminor component, often from about 0.05 to 10% by weight, with theremainder being the base component.

[0434] In all of the above pharmaceutical compositions, the compounds ofthe invention are formulated with an acceptable carrier or excipient.The carriers or excipients used must, of course, be acceptable in thesense of being compatible with the other ingredients of the compositionand must not be deleterious to the patient. The carrier or excipient canbe a solid or a liquid, or both, and is preferably formulated with thecompound of the invention as a unit-dose composition, for example, atablet, which can contain from 0.05% to 95% by weight of the activecompound. Such carriers or excipients include inert fillers or diluents,binders, lubricants, disintegrating agents, solution retardants,resorption accelerators, absorption agents, and coloring agents.Suitable binders include starch, gelatin, natural sugars such as glucoseor β-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride, and the like. Disintegrators include starch,methyl cellulose, agar, bentonite, xanthan gum, and the like.

[0435] Generally, a therapeutically effective daily dose is from about0.001 mg to about 15 mg/kg of body weight per day of a compound of theinvention; preferably, from about 0.1 mg to about 10 mg/kg of bodyweight per day; and most preferably, from about 0.1 mg to about 1.5mg/kg of body weight per day. For example, for administration to a 70 kgperson, the dosage range would be from about 0.07 mg to about 1050 mgper day of a compound of the invention, preferably from about 7.0 mg toabout 700 mg per day, and most preferably from about 7.0 mg to about 105mg per day. Some degree of routine dose optimization may be required todetermine an optimal dosing level and pattern.

[0436] Pharmaceutically acceptable carriers and excipients encompass allthe foregoing additives and the like.

[0437] Examples of Pharmaceutical Formulations A. TABLETS ComponentAmount per tablet (mg) active substance 100 lactose 140 corn starch 240polyvinylpyrrolidone 15 magnesium stearate 5 TOTAL 500

[0438] The finely ground active substance, lactose, and some of the cornstarch are mixed together. The mixture is screened, then moistened witha solution of polyvinylpyrrolidone in water, kneaded, wet-granulated anddried. The granules, the remaining corn starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toproduce tablets of suitable shape and size. B. TABLETS Component Amountper tablet (mg) active substance 80 lactose 55 corn starch 190polyvinylpyrrolidone 15 magnesium stearate 2 microcrystalline cellulose35 sodium-carboxymethyl starch 23 TOTAL 400

[0439] The finely ground active substance, some of the corn starch,lactose, microcrystalline cellulose, and polyvinylpyrrolidone are mixedtogether, the mixture is screened and worked with the remaining cornstarch and water to form a granulate which is dried and screened. Thesodium-carboxymethyl starch and the magnesium stearate are added andmixed in and the mixture is compressed to form tablets of a suitablesize. C. COATED TABLETS Component Amount per tablet (mg) activesubstance 5 lactose 30 corn starch 41.5 polyvinylpyrrolidone 3 magnesiumstearate 0.5 TOTAL 90

[0440] The active substance, corn starch, lactose, andpolyvinylpyrrolidone are thoroughly mixed and moistened with water. Themoist mass is pushed through a screen with a 1 mm mesh size, dried atabout 45° C. and the granules are then passed through the same screen.After the magnesium stearate has been mixed in, convex tablet cores witha diameter of 6 mm are compressed in a tablet-making machine. The tabletcores thus produced are coated in known manner with a coveringconsisting essentially of sugar and talc. The finished coated tabletsare polished with wax. D. CAPSULES Component Amount per capsule (mg)active substance 50 corn starch 268.5 magnesium stearate 1.5 TOTAL 320

[0441] The substance and corn starch are mixed and moistened with water.The moist mass is screened and dried. The dry granules are screened andmixed with magnesium stearate. The finished mixture is packed into size1 hard gelatine capsules. E. AMPOULE SOLUTION Component Amount perampoule active substance 50 mg sodium chloride 50 mg water for inj.  5mL

[0442] The active substance is dissolved in water at its own pH oroptionally at pH 5.5 to 6.5 and sodium chloride is added to make itisotonic. The solution obtained is filtered free from pyrogens and thefiltrate is transferred under aseptic conditions into ampoules which arethen sterilized and sealed by fusion. The ampoules contain 5 mg, 25 mg,and 50 mg of active substance. F. SUPPOSITORIES Component Amount persuppository (mg) active substance 50 solid fat 1650 TOTAL 1700

[0443] The hard fat is melted. At 40° C., the ground active substance ishomogeneously dispersed therein. The mixture is cooled to 38° C. andpoured into slightly chilled suppository molds. G. METERING AEROSOLComponent Amount active substance 0.005 sorbitan trioleate 0.1monofluorotrichloromethane and to 100 difluorodichloromethane (2:3)

[0444] The suspension is transferred into a conventional aerosolcontainer with a metering valve. Preferably, 50 μL of suspension aredelivered per spray. The active substance may also be metered in higherdoses if desired (e.g., 0.02% by weight). Component Amount H. POWDER FORINHALATION active substance 1.0 mg lactose monohydrate to 25 mg I.POWDER FOR INHALATION active substance 2.0 mg lactose monohydrate to 25mg J. POWDER FOR INHALATION active substance 1.0 mg lactose monohydrateto 5 mg K. POWDER FOR INHALATION active substance 2.0 mg lactosemonohydrate to 5 mg

[0445] In Examples H, I, J, and K, the powder for inhalation is producedin the usual way by mixing the individual ingredients together.

We claim:
 1. A compound of Formula (IA):

wherein: R¹ is an aryl or heteroaryl group, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R¹ is independently C₁-C₅ alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, heteroaryl, C₁-C₅ alkoxy, C₂-C₅ alkenyloxy, C₂-C₅ alkynyloxy, aryloxy, acyl, C₁-C₅ alkoxycarbonyl, C₁-C₅ alkanoyloxy, aminocarbonyl, C₁-C₅ alkylaminocarbonyl, C₁-C₅ dialkylaminocarbonyl, aminocarbonyloxy, C₁-C₅ alkylaminocarbonyloxy, C₁-C₅ dialkylaminocarbonyloxy, C₁-C₅ alkanoylamino, C₁-C₅ alkoxycarbonylamino, C₁-C₅ alkylsulfonylamino, aminosulfonyl, C₁-C₅ alkylaminosulfonyl, C₁-C₅ dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, or amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C₁-C₅ alkyl or aryl; or ureido wherein either nitrogen atom is optionally independently substituted with C₁-C₅ alkyl; or C₁-C₅ alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone; wherein each substituent group of R¹ is optionally independently substituted with one to three substituent groups selected from C₁-C₃ alkyl, C₁-C₃ alkoxy, halogen, hydroxy, oxo, cyano or amino; R² and R³ are each independently hydrogen or C₁-C₅ alkyl, or R² and R³ together with the carbon atom they are commonly attached to form a C₃-C₈ spiro cycloalkyl ring; R⁴ is C₁-C₅ alkyl, C₂-C₅ alkenyl, or C₂-C₅ alkynyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁴ is independently C₁-C₃ alkyl, hydroxy, halogen, amino, or oxo; and R⁵ is a heteroaryl group optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁵ is independently C₁-C₅ alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, heteroaryl, C₁-C₅ alkoxy, C₂-C₅ alkenyloxy, C₂-C₅ alkynyloxy, aryloxy, acyl, C₁-C₅ alkoxycarbonyl, C₁-C₅ alkanoyloxy, aminocarbonyl, C₁-C₅ alkylaminocarbonyl, C₁-C₅ dialkyl-aminocarbonyl, aminocarbonyloxy, C₁-C₅ alkylaminocarbonyloxy, C₁-C₅ dialkyl-aminocarbonyloxy, C₁-C₅ alkanoylamino, C₁-C₅ alkoxycarbonylamino, C₁-C₅ alkylsulfonylamino, aminosulfonyl, C₁-C₅ alkylaminosulfonyl, C₁-C₅ dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, or amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C₁-C₅ alkyl; or ureido wherein either nitrogen atom is optionally independently substituted with C₁-C₅ alkyl; or C₁-C₅ alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of R⁵ is optionally independently substituted with one to three substituent groups selected from C₁-C₃ alkyl, C₁-C₃ alkoxy, halogen, hydroxy, oxo, cyano, amino, or trifluoromethyl, R⁶ and R⁷ are each independently hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, C₂₋₈ alkenyloxy, C₂₋₈ alkynyloxy, hydroxy, carbocyclyl, heterocyclyl, aryl, aryloxy, acyl, heteroaryl, carbocycle-C₁-C₈ alkyl, aryl-C₁-C₈ alkyl, aryl-C₁-C₈ haloalkyl, heterocyclyl-C₁-C₈ alkyl, heteroaryl-C₁-C₈ alkyl, carbocycle-C₂-C₈ alkenyl, aryl-C₂-C₈ alkenyl, heterocyclyl-C₂-C₈ alkenyl, heteroaryl-C₂-C₈ alkenyl, or C₁-C₅ alkylthio wherein the sulfur atom is oxidized to a sulfoxide or sulfone, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁶ and R⁷ are independently C₁-C₅ alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈ cycloalkyl, phenyl, C₁-C₅ alkoxy, phenoxy, C₁-C₅ alkanoyl, aroyl, C₁-C₅ alkoxycarbonyl, C₁-C₅ alkanoyloxy, aminocarbonyl, C₁-C₅ alkylaminocarbonyl, C₁-C₅ dialkylaminocarbonyl, aminocarbonyloxy, C₁-C₅ alkylaminocarbonyloxy, C₁-C₅ dialkylaminocarbonyloxy, C₁-C₅ alkanoylamino, C₁-C₅ alkoxycarbonylamino, C₁-C₅ alkylsulfonylamino, aminosulfonyl, C₁-C₅ alkylaminosulfonyl, C₁-C₅ dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, oxo, trifluoromethyl, trifluoromethoxy, nitro; or amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C₁-C₅ alkyl; or ureido wherein either nitrogen atom is optionally independently substituted with C₁-C₅ alkyl; or C₁-C₅ alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone; or a tautomer, prodrug, solvate, or salt thereof.
 2. The compound of Formula (IA) according to claim 1, wherein: R¹ is phenyl, naphthyl, indanyl, indenyl, dihydrobenzofuranyl, benzofuranyl, chromanyl, dihydroindolyl, indolyl, dihydrobenzothienyl, benzothienyl, benzodioxolanyl, dihydrobenzoxazolyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, thienyl, furanyl, pyrrolyl, pyridinyl, pyrimidinyl, or pyrazinyl each optionally independently substituted with one to three substituent groups, wherein each substituent group of R¹ is independently C₁-C₃ alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, C₂-C₃ alkenyloxy, C₁-C₃ alkanoyl, C₁-C₃ alkoxycarbonyl, C₁-C₃ alkanoyloxy, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, or C₁-C₃ alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone; wherein each substituent group of R¹ is independently optionally substituted with a substituent group selected from methyl, methoxy, halogen, hydroxy, oxo, cyano, or amino; R² and R³ are each independently hydrogen or C₁-C₃ alkyl, or R² and R³ together with the carbon atom they are commonly attached to form a C₃-C₆ spiro cycloalkyl ring; R⁴ is C₁-C₃ alkyl or C₂-C₃ alkenyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁴ is independently methyl, hydroxy, fluoro, chloro, bromo, or oxo; and R⁵ is an imidazolyl, pyridinyl, indolyl, azaindolyl, diazaindolyl, benzofuranyl, furanopyridinyl, furanopyrimidinyl, benzothienyl, thienopyridinyl, thienopyrimidinyl, benzoxazolyl, oxazolopyridinyl, benzothiazolyl, thiazolopyridinyl, benzimidazolyl, imidazolopyridinyl, quinolinyl, or isoquinolinyl group, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁵ is independently C₁-C₃ alkyl, C₂-C₃ alkenyl, phenyl, C₁-C₃ alkoxy, methoxycarbonyl, aminocarbonyl, C₁-C₃ alkylaminocarbonyl, C₁-C₃ dialkylaminocarbonyl, heterocyclylcarbonyl, hydroxy, fluoro, chloro, bromo, cyano, trifluoromethyl, or C₁-C₃ alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of R⁵ is optionally independently substituted with a substituent group selected from methyl, methoxy, hydroxy, fluoro, chloro, bromo, oxo, or trifluoromethyl, R⁶ and R⁷ are each independently hydrogen, C₁₋₅ alkyl, C₁₋₅ alkoxy, C₂₋₅ alkenyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, phenethyl, phenoxy, hydroxy or C₁₋₅ alkylthio wherein the sulfur atom is oxidized to a sulfoxide or sulfone, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁶ and R⁷ are independently methyl, methoxy, hydroxy, halogen, cyano, oxo or trifluoromethyl; or a tautomer, prodrug, solvate, or salt thereof.
 3. The compound of Formula (IA) according to claim 1, wherein: R¹ is thienyl, phenyl, naphthyl, pyridinyl, chromanyl, dihydrobenzofuranyl, or benzofuranyl, each optionally independently substituted with one or two substituent groups, wherein each substituent group of R¹ is independently methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, hydroxy, trifluoromethyl, trifluoromethoxy, oxo or cyano; R² and R³ are each independently C₁-C₃ alkyl, or R² and R³ together with the carbon atom they are commonly attached to form a spiro cyclopropyl or cyclobutyl ring; R⁴ is C₁-C₃ alkyl; and R⁵ is a pyridinyl, indolyl, azaindolyl, benzofuranyl, furanopyridinyl, benzothienyl, thienopyridinyl, benzoxazolyl, benzimidazolyl, quinolinyl, or isoquinolinyl group, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁵ is independently methyl, phenyl, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, morpholinylcarbonyl, methoxy, hydroxy, fluoro, chloro, bromo, cyano, or trifluoromethyl, R⁶ and R⁷ are each independently hydrogen, C₁₋₅ alkyl, benzyl, hydroxy or C₁-C₅ alkylthio wherein the sulfur atom is oxidized to a sulfoxide or sulfone, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁶ and R⁷ are independently methyl or oxo; or a tautomer, prodrug, solvate, or salt thereof.
 4. The compound of Formula (IA) according to claim 1, wherein: R¹ is phenyl, dihydrobenzofuranyl, benzofuranyl or pyridinyl substituted with one or two substituent groups, wherein each substituent group of R¹ is independently methyl, methoxy, fluoro, chloro, bromo, trifuoromethyl, trifluoromethoxy, cyano or hydroxy; R² and R³ are each independently C₁-C₃ alkyl; R⁴ is CH₂; and R⁵ is a pyridinyl, indolyl, azaindolyl, benzimidazolyl, quinolinyl, or isoquinolinyl group, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁵ is independently methyl, fluoro, chloro, cyano or trifluoromethyl, R⁶ and R⁷ are each independently hydrogen, methyl, ethyl, propyl, butyl, isobutyl, acetyl, formyl, methylsulfonyl or hydroxy, or a tautomer, prodrug, solvate, or salt thereof.
 5. The compound of Formula (IA) according to claim 1, wherein: R¹ is a pyridinyl, is a phenyl substituted with a fluoro, is a phenyl substituted with a methoxy group and a fluoro, is a phenyl substituted with a hydroxy group and a fluoro, is a benzofuranyl group, is a dihydrobenzofuranyl group or is a dihydrobenzofuranyl group substituted with a cyano group, R² and R³ are each independently methyl; R⁴is CH₂; and R⁵ is a quinolinyl, azaindolyl, pyridinyl, benzimidazolyl or indolyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁵ is independently methyl, fluoro, chloro, trifluoromethyl or cyano, R⁶ and R⁷ are each independently hydrogen, methyl, ethyl, propyl, butyl, isobutyl, acetyl, formyl, methylsulfonyl or hydroxy, or a tautomer, prodrug, solvate, or salt thereof.
 6. The compound of Formula (IA) according to claim 1, wherein: R¹ is an aryl or heteroaryl group, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R¹ is independently C₁-C₅ alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈ cycloalkyl, aryl, C₁-C₅ alkoxy, C₂-C₅ alkenyloxy, C₂-C₅ alkynyloxy, aryloxy, acyl, C₁-C₅ alkoxycarbonyl, C₁-C₅ alkanoyloxy, aminocarbonyl, C₁-C₅ alkylaminocarbonyl, di-C₁-C₅alkyl-aminocarbonyl, aminocarbonyloxy, C₁-C₅ alkylaminocarbonyloxy, di-C₁-C₅alkyl-aminocarbonyloxy, C₁-C₅ alkanoylamino, C₁-C₅ alkoxycarbonylamino, C₁-C₅ alkylsulfonylamino, C₁-C₅ alkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, nitro, or amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C₁-C₅ alkyl or aryl; or ureido wherein either nitrogen atom is optionally independently substituted with C₁-C₅ alkyl; or C₁-C₅ alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone; wherein each substituent group of R¹ is independently optionally substituted with one to three substituent groups selected from C₁-C₃alkyl, C₁-C₃alkoxy, halogen, hydroxy, oxo, cyano or amino; R² and R³ are each independently hydrogen or C₁-C₅ alkyl, or R² and R³ together with the carbon atom they are commonly attached to form a C₃-C₈ spiro cycloalkyl ring; R⁴ is C₁-C₅ alkyl, C₂-C₅ alkenyl, or C₂-C₅ alkynyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁴ is independently C₁-C₃ alkyl, hydroxy, halogen, or oxo; R⁵ is a heteroaryl group optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁵ is independently C₁-C₅ alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, heteroaryl, C₁-C₅ alkoxy, C₂-C₅ alkenyloxy, C₂-C₅ alkynyloxy, aryloxy, acyl, C₁-C₅ alkoxycarbonyl, C₁-C₅ alkanoyloxy, aminocarbonyl, C₁-C₅ alkylaminocarbonyl, di-C₁-C₅alkyl-aminocarbonyl, aminocarbonyloxy, C₁-C₅ alkylaminocarbonyloxy, di-C₁-C₅alkyl-aminocarbonyloxy, C₁-C₅ alkanoylamino, C₁-C₅ alkoxycarbonylamino, C₁-C₅ alkylsulfonylamino, C₁-C₅ alkylaminosulfonyl, di-C₁-C₅ alkyl-aminosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, or amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C₁-C₅ alkyl; or ureido wherein either nitrogen atom is optionally independently substituted with C₁-C₅ alkyl; or C₁-C₅ alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of R⁵ is optionally independently substituted with one to three substituent groups selected from C₁-C₃ alkyl, C₁-C₃ alkoxy, halogen, hydroxy, oxo, cyano, amino, or trifluoromethyl; and R⁶ and R⁷ are hydrogen; or a tautomer, prodrug, solvate, or salt thereof.
 7. The compound of Formula (IA) according to claim 1, wherein: R¹ is phenyl, naphthyl, indanyl, indenyl, dihydrobenzofuranyl, dihydroindolyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, thienyl, furanyl, pyrrolyl, pyridinyl, pyrazinyl, pyrimidinyl, indolyl, benzofuranyl or benzothienyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R¹ is independently C₁-C₃ alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, C₂-C₃ alkenyloxy, C₁-C₃ alkanoyl, C₁-C₃ alkoxycarbonyl, C₁-C₃ alkanoyloxy, halogen, hydroxy, carboxy, cyano, trifluoromethyl, nitro, or C₁-C₃ alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone; wherein each substituent group of R¹ is independently optionally substituted with a substituent group selected from methyl, methoxy, halogen, hydroxy, oxo, cyano, or amino; R² and R³are each independently hydrogen or C₁-C₃ alkyl, or R² and R³ together with the carbon atom they are commonly attached to form a C₃-C₆ spiro cycloalkyl ring; R⁴ is C₁-C₃ alkyl or C₂-C₃ alkenyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁴ is independently methyl, hydroxy, fluoro, chloro, bromo, or oxo; R⁵ is a pyridyl, indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, quinolinyl, or isoquinolinyl group, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁵ is independently C₁-C₃ alkyl, C₂-C₃ alkenyl, phenyl, C₁-C₃ alkoxy, fluoro, chloro, bromo, cyano, trifluoromethyl, or C₁-C₃ alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of R⁵ is optionally independently substituted with a substituent group selected from methyl, methoxy, fluoro, chloro, bromo, or trifluoromethyl, and R⁶ and R⁷ are hydrogen; or a tautomer, prodrug, solvate, or salt thereof.
 8. The compound of Formula (IA) according to claim 1, wherein: R¹ is phenyl, pyridinyl, dihydrobenzofuranyl, or benzofuranyl, each optionally independently substituted with one or two substituent groups, wherein each substituent group of R¹is independently methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, hydroxy, or cyano; R² and R³ are each independently C₁-C₃ alkyl, or R² and R³ together with the carbon atom they are commonly attached to form a spiro cyclopropyl or cyclobutyl ring; R⁴ is C₁-C₃ alkyl; R⁵ is a pyridyl, indolyl, benzofuranyl, benzoxazolyl, benzimidazolyl, quinolinyl, or isoquinolinyl group, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁵ is independently methyl, phenyl, fluoro, chloro, cyano, or trifluoromethyl; and R⁶ and R⁷ are hydrogen; or a tautomer, prodrug, solvate, or salt thereof.
 9. The compound of Formula (IA) according to claim 1, wherein: R¹ is phenyl substituted with one or two substituent groups, wherein each substituent group of R¹ is independently methoxy, fluoro, chloro, bromo or hydroxy; R² and R³ are each independently C₁-C₃ alkyl; R⁴is CH₂; R⁵ is a pyridyl, indolyl, benzimidazolyl, quinolinyl, or isoquinolinyl group, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁵ is independently methyl, fluoro, chloro, or trifluoromethyl, and R⁶ and R⁷ are hydrogen; or a tautomer, prodrug, solvate, or salt thereof.
 10. The compound of Formula (IA) according to claim 1, wherein: R¹ is phenyl substituted with a methoxy group and a fluoro, or is a phenyl substituted with a hydroxy group and a fluoro, R² and R³ are each independently methyl; R⁴ is CH₂; R⁵ is a pyridyl or indolyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁵ is independently methyl, fluoro or chloro; and R⁶ and R⁷ are hydrogen; or a tautomer, prodrug, solvate, or salt thereof.
 11. A compound according to claim 1 selected from: 3-(5-Fluoro-2-methoxy-phenyl)-3-methyl-1-pyridin-2-ylmethyl-1-trifluoromethyl-butylamine; 3-(5-Fluoro-2-methoxy-phenyl)-1-(1H-indol-2-ylmethyl)-3-methyl-1-trifluoromethyl-butylamine; 1-(2,6-Dichloro-pyridin-4-ylmethyl)-3-(5-fluoro-2-methoxy-phenyl)-3-methyl-1-trifluoromethyl-butylamine; 1-(4,6-Dimethyl-pyridin-2-ylmethyl)-3-(5-fluoro-2-methoxy-phenyl)-3-methyl-1-trifluoromethyl-butylamine; 1-(2-Chloro-pyridin-4-ylmethyl)-3-(5-fluoro-2-methoxy-phenyl)-3-methyl-1-trifluoromethyl-butylamine; 3-(5-Fluoro-2-methyl-phenyl)-3-methyl-1-(3-methyl-1H-indol-2-ylmethyl)-1-trifluoromethyl-butylamine; 3-(5-Fluoro-2-methoxy-phenyl)-3-methyl-1-(3-methyl-1H-indol-2-ylmethyl)-1-trifluoromethyl-butylamine; 1-(6-Fluoro-1H-indol-2-ylmethyl)-3-(5-fluoro-2-methoxy-phenyl)-3-methyl-1-trifluoromethyl-butylamine; 3-(4-Fluoro-phenyl)-3-methyl-1-(3-methyl-1H-indol-2-ylmethyl)-1-trifluoromethyl-buytyalmine; 3-Benzofuran-7-yl-1-(2,6-dichloro-pyridin-4-ylmethyl)-3-methyl-1-trifluoromethyl-butylamine; 3-(2,3-Dihydro-benzofuran-7-yl)-1-(6-fluoro-1H-indol-2-ylmethyl)-3-methyl-1-trifluoromethyl-butylamine; 3-(5-Fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butylamine; 1-(2-Chloro-quinolin-4-ylmethyl)-3-(5-fluoro-2-methyl-phenyl)-3-methyl-1-trifluoromethyl-butylamine; 3-(4-Fluoro-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butylamine; 7-[3-Amino-3-(1H-benzoimidazol-2-ylmethyl)-4,4,4-trifluoro-1,1-dimethyl-butyl]-2,3-dihydro-benzofuran-5-carbonitrile; 1-(6-Fluoro-1H-benzoimidazol-2-ylmethyl)-3-(5-fluoro-2-methyl-phenyl)-3-methyl-1-trifluoromethyl-butylamine; 2-[3-Amino-3-(1H-benzoimidazol-2-ylmethyl)-4,4,4-trifluoro-1,1-dimethyl-butyl]-4-fluoro-phenol; 1-(1H-Benzoimidazol-2-ylmethyl)-3-(4-fluoro-phenyl)-3-methyl-1-trifluoromethyl-butylamine; 1-(1H-Indol-2-ylmethyl)-3-methyl-3-pyridin-3-yl-1-trifluoromethyl-butylamine; 1-(1H-Benzoimidazol-2-ylmethyl)-3-methyl-3-pyridin-4-yl-1-trifluoromethyl-butylamine; 3-Methyl-1-(3-methyl-1H-indol-2-ylmethyl)-3-pyridin-3-yl-1-trifluoromethyl-butylamine; 1-(6-Fluoro-1H-indol-2-ylmethyl)-3-methyl-3-pyridin-3-yl-1-trifluoromethyl-butylamine; 3-(2,3-Dihydro-benzofuran-7-yl)-1-(1H-indol-2-ylmethyl)-3-methyl-1-trifluoromethyl-butylamine; [3-(5-Fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butyl]-methyl-amine; Ethyl-[3-(5-fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butyl]-amine; [3-(5-Fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butyl]-propyl-amine; [3-(5-Fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluorometbyl-butyl]-isobutyl-amine; Butyl-[3-(5-fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butyl]-amine; [3-(5-Fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butyl]-dimethyl-amine; N-[3-(5-Fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butyl]-acetamide; N-[3-(5-Fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butyl]-formamide; N-[3-(5-Fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butyl]-methanesulfonamide; 1-(2,6-Dimethyl-pyridin-4-ylmethyl)-3-(5-fluoro-2-methoxy-phenyl)-3-methyl-1-trifluoromethyl-butylamine; 3-(5-Fluoro-2-methoxy-phenyl)-3-methyl-1-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-1-trifluoromethyl-butylamine; 2-[2-Amino-4-(5-fluoro-2-methoxy-phenyl)-4-methyl-2-trifluoromethyl-pentyl]-4-methyl-1H-indole-6-carbonitrile; N-[3-(5-Fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butyl]-hydroxylamine; and 2-(3-Amino-4,4,4-trifluoro-1,1-dimethyl-3-quinolin-4-ylmethyl-butyl)-4-fluoro-phenol; or the tautomers, prodrugs, solvates, or salts thereof.
 12. A compound according to claim 1 selected from: 3-(5-Fluoro-2-methoxy-phenyl)-3-methyl-1-pyridin-2-ylmethyl-1-trifluoromethyl-butylamine; 3-(5-Fluoro-2-methoxy-phenyl)-1-(1H-indol-2-ylmethyl)-3-methyl-1-trifluoromethyl-butylamine; 1-(2,6-Dichloro-pyridin-4-ylmethyl)-3-(5-fluoro-2-methoxy-phenyl)-3-methyl-1-trifluoromethyl-butylamine; 1-(4,6-Dimethyl-pyridin-2-ylmethyl)-3-(5-fluoro-2-methoxy-phenyl)-3-methyl-1-trifluoromethyl-butylamine; 1-(2-Chloro-pyridin-4-ylmethyl)-3-(5-fluoro-2-methoxy-phenyl)-3-methyl-1-trifluoromethyl-butylamine; 3-(5-Fluoro-2-methyl-phenyl)-3-methyl-1-(3-methyl-1H-indol-2-ylmethyl)-1-trifluoromethyl-butylamine; 3-(5-Fluoro-2-methoxy-phenyl)-3-methyl-1-(3-methyl-1H-indol-2-ylmethyl)-1-trifluoromethyl-butylamine; 1-(6-Fluoro-1H-indol-2-ylmethyl)-3-(5-fluoro-2-methoxy-phenyl)-3-methyl-1-trifluoromethyl-butylamine; 3-(4-Fluoro-phenyl)-3-methyl-1-(3-methyl-1H-indol-2-ylmethyl)-1-trifluoromethyl-butylamine; 3-Benzofuran-7-yl-1-(2,6-dichloro-pyridin-4-ylmethyl)-3-methyl-1-trifluoromethyl-butylamine; 3-(2,3-Dihydro-benzofuran-7-yl)-1-(6-fluoro-1H-indol-2-ylmethyl)-3-methyl-1-trifluoromethyl-butylamine; 3-(5-Fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butylamine; 1-(2-Chloro-quinolin-4-ylmethyl)-3-(5-fluoro-2-methyl-phenyl)-3-methyl-1-trifluoromethyl-butylamine; 3-(4-Fluoro-phenyl)-3-methyl-1-quinolin-4-ylmethyl-1-trifluoromethyl-butylamine; 7-[3-Amino-3-(1H-benzoimidazol-2-ylmethyl)-4,4,4-trifluoro-1,1-dimethyl-butyl]-2,3-dihydro-benzofuran-5-carbonitrile; 1-(6-Fluoro-1H-benzoimidazol-2-ylmethyl)-3-(5-fluoro-2-methyl-phenyl)-3-methyl-1-trifluoromethyl-butylamine; 2-[3-Amino-3-(1H-benzoimidazol-2-ylmethyl)-4,4,4-trifluoro-1,1-dimethyl-butyl]-4-fluoro-phenol; 1-(1H-Benzoimidazol-2-ylmethyl)-3-(4-fluoro-phenyl)-3-methyl-1-trifluoromethyl-butylamine; 1-(1H-Indol-2-ylmethyl)-3-methyl-3-pyridin-3-yl-1-trifluoromethyl-butylamine; 1-(1H-Benzoimidazol-2-ylmethyl)-3-methyl-3-pyridin-4-yl-1-trifluoromethyl-butylamine; 3-Methyl-1-(3-methyl-1H-indol-2-ylmethyl)-3-pyridin-3-yl-1-trifluoromethyl-butylamine; 1-(6-Fluoro-1H-indol-2-ylmethyl)-3-methyl-3-pyridin-3-yl-1-trifluoromethyl-butylamine; 3-(2,3-Dihydro-benzofuran-7-yl)-1-(1H-indol-2-ylmethyl)-3-methyl-1-trifluoromethyl-butylamine; or the tautomers, prodrugs, solvates, or salts thereof.
 13. A pharmaceutical composition comprising an effective amount of a compound according to claim 1, or a tautomer, prodrug, solvate, or salt thereof, and a pharmaceutically acceptable excipient or carrier.
 14. A method of modulating the glucocorticoid receptor function in a patient, the method comprising administering to the patient an effective amount of a pharmaceutically acceptable compound according to claim 1, or a tautomer, prodrug, solvate, or salt thereof.
 15. A method of treating a disease-state or condition mediated by the glucocorticoid receptor function in a patient in need of such treatment, the method comprising administering to the patient an effective amount of a pharmaceutically acceptable compound according to claim 1, or a tautomer, prodrug, solvate, or salt thereof.
 16. A method of treating a disease-state or condition selected from: type II diabetes, obesity, cardiovascular diseases, hypertension, arteriosclerosis, neurological diseases, adrenal and pituitary tumors, and glaucoma, in a patient in need of such treatment, the method comprising administering to the patient an effective amount of a pharmaceutically acceptable compound according to claim 1, or a tautomer, prodrug, solvate, or salt thereof.
 17. A method of treating a disease characterized by inflammatory, allergic, or proliferative processes, in a patient in need of such treatment, the method comprising administering to the patient an effective amount of a pharmaceutically acceptable compound according to claim 1, or a tautomer, prodrug, solvate, or salt thereof.
 18. The method according to claim 17, wherein the disease is selected from: (i) lung diseases; (ii) rheumatic diseases or autoimmune diseases or joint diseases; (iii) allergic diseases; (iv) vasculitis diseases; (v) dermatological diseases; (vi) renal diseases; (vii) hepatic diseases; (viii) gastrointestinal diseases; (ix) proctological diseases; (x) eye diseases; (xi) diseases of the ear, nose, and throat (ENT) area; (xii) neurological diseases; (xiii) blood diseases; (xiv) tumor diseases; (xv) endocrine diseases; (xvi) organ and tissue transplantations and graft-versus-host diseases; (xvii) severe states of shock; (xviii) substitution therapy; and (xix) pain of inflammatory genesis.
 19. The method according to claim 17, wherein the disease is selected from: type I diabetes, osteoarthritis, Guillain-Barre syndrome, restenosis following percutaneous transluminal coronary angioplasty, Alzheimer disease, acute and chronic pain, atherosclerosis, reperfusion injury, bone resorption diseases, congestive heart failure, myocardial infarction, thermal injury, multiple organ injury secondary to trauma, acute purulent meningitis, necrotizing enterocolitis, and syndromes associated with hemodialysis, leukopheresis, and granulocyte transfusion.
 20. A method of treating a disease-state or condition mediated by the glucocorticoid receptor function in a patient in need of such treatment, the method comprising sequentially or simultaneously administering to the patient: (a) an effective amount of a pharmaceutically acceptable compound according to claim 1, or a tautomer, prodrug, solvate, or salt thereof; and (b) a pharmaceutically acceptable glucocorticoid.
 21. A kit for the in vitro diagnostic determination of the glucocorticoid receptor function in a sample, comprising: (a) a diagnostically effective amount of a compound according to claim 1 or a tautomer, prodrug, solvate, or salt thereof; and (b) instructions for use of the diagnostic kit.
 22. A method of making a compound of Formula (IA) according to claim 1 wherein R⁶ and R⁷ are both hydrogen:

where R¹, R², R³, R⁴, and R⁵ are as defined in claim 1, the method comprising: reacting a compound of Formula (V) with an organometallic reagent R⁵R⁴M where M is Li or MgX and X is Cl, Br, or I, in a suitable solvent to form the compound of Formula (IA):

where R is alkyl and R¹, R², R³, R⁴, and R⁵ are as defined in claim
 1. 23. A method of making a compound of Formula (IA) according to claim 1 wherein R⁶ and R⁷ are both hydrogen:

where R¹, R², R³, R⁴, and R⁵ are as defined in claim 1, the method comprising: (a) reacting an ester of Formula (II) with a suitable reducing agent in a suitable solvent to form a diol of Formula (III)

(b) reacting the diol of Formula (III) under suitable oxidative cleavage conditions to form a ketone of Formula (IV)

(c) reacting the ketone of Formula (IV) with a suitable Lewis acid and an alkylsulfinamide of formula RS(O)NH₂ where R is alkyl to form the compound of Formula (V)

(d) reacting a compound of Formula (V) with an organometallic reagent R⁵R⁴M where M is Li or MgX and X is Cl, Br, or I, in a suitable solvent to form the compound of Formula (IA):

(a′) reacting the trifluoroacetamide of Formula (XII) with a vinyl magnesium bromide bearing R² and R³ of the formula R²R³CH═CHMgBr in a suitable solvent to provide the trifluoromethylenone of Formula (XIII)

(b′) reacting the trifluoromethylenone of Formula (XIII) with a suitable organocopper reagent generated from an organometallic reagent R¹M where M is Li or MgX and a copper salt CuX, where X is Cl, Br or I, in a suitable solvent to form the ketone of Formula (IV)

and performing steps (c) and (d) as set forth above to form the compound of Formula (IA); where R is alkyl and R¹, R², R³, R⁴, and R⁵ are as defined in claim
 1. 24. A compound of Formula (IB):

wherein: R¹ is an aryl or heteroaryl group, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R¹ is independently C₁-C₅ alky, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, heteroaryl, C₁-C₅ alkoxy, C₂-C₅ alkenyloxy, C₂-C₅ alkynyloxy, aryloxy, acyl, C₁-C₅ alkoxycarbonyl, C₁-C₅ alkanoyloxy, aminocarbonyl, C₁-C₅ alkylaminocarbonyl, C₁-C₅ dialkylaminocarbonyl, aminocarbonyloxy, C₁-C₅ alkylaminocarbonyloxy, C₁-C₅ dialkylaminocarbonyloxy, C₁-C₅ alkanoylamino, C₁-C₅ alkoxycarbonylamino, C₁-C₅ alkylsulfonylamino, aminosulfonyl, C₁-C₅ alkylaminosulfonyl, C₁-C₅ dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, or amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C₁-C₅ alkyl or aryl; or ureido wherein either nitrogen atom is optionally independently substituted with C₁-C₅ alkyl; or C₁-C₅ alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone; wherein each substituent group of R¹ is independently optionally substituted with one to three substituent groups selected from C₁-C₃ alkyl, C₁-C₃ alkoxy, halogen, hydroxy, oxo, cyano or amino. R² and R³ are each independently hydrogen or C₁-C₅ alkyl, or R² and R³ together with the carbon atom they are commonly attached to form a C₃-C₈ spiro cycloalkyl ring; R⁴ is C₁-C₅ alkyl, C₂-C₅ alkenyl, or C₂-C₅ alkynyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁴ is independently C₁-C₃ alkyl, hydroxy, halogen, amino, or oxo; R⁵ is a heteroaryl group optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁵ is independently C₁-C₅ alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, heteroaryl, C₁-C₅ alkoxy, C₂-C₅ alkenyloxy, C₂-C₅ alkynyloxy, aryloxy, acyl, C₁-C₅ alkoxycarbonyl, C₁-C₅ alkanoyloxy, aminocarbonyl, C₁-C₅ alkylaminocarbonyl, C₁-C₅ dialkyl-aminocarbonyl, aminocarbonyloxy, C₁-C₅ alkylaminocarbonyloxy, C₁-C₅ dialkyl-aminocarbonyloxy, C₁-C₅ alkanoylamino, C₁-C₅ alkoxycarbonylamino, C₁-C₅ alkylsulfonylamino, aminosulfonyl, C₁-C₅ alkylaminosulfonyl, C₁-C₅ dialkyl-aminosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, or amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C₁-C₅ alkyl; or ureido wherein either nitrogen atom is optionally independently substituted with C₁-C₅ alkyl; or C₁-C₅ alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of R⁵ is optionally independently substituted with one to three substituent groups selected from C₁-C₃ alkyl, C₁-C₃ alkoxy, halogen, hydroxy, oxo, cyano, amino, or trifluoromethyl; R⁶ and R⁷ are each independently hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₁₋₈ alkoxy, C₂₋₈ alkenyloxy, C₂₋₈ alkynyloxy, hydroxy, carbocyclyl, heterocyclyl, aryl, aryloxy, acyl, heteroaryl, carbocycle-C₁-C₈ alkyl, aryl-C₁-C₈ alkyl, aryl-C₁-C₈ haloalkyl, heterocyclyl-C₁-C₈ alkyl, heteroaryl-C₁-C₈ alkyl, carbocycle-C₂-C₈ alkenyl, aryl-C₂-C₈ alkenyl, heterocyclyl-C₂-C₈ alkenyl, heteroaryl-C₂-C₈ alkenyl, or C₁-C₅ alkylthio wherein the sulfur atom is oxidized to a sulfoxide or sulfone, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁶ and R⁷ are independently C₁-C₅ alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈ cycloalkyl, phenyl, C₁-C₅ alkoxy, phenoxy, C₁-C₅ alkanoyl, aroyl, C₁-C₅ alkoxycarbonyl, C₁-C₅ alkanoyloxy, aminocarbonyl, C₁-C₅ alkylaminocarbonyl, C₁-C₅ dialkylaminocarbonyl, aminocarbonyloxy, C₁-C₅ alkylaminocarbonyloxy, C₁-C₅ dialkylaminocarbonyloxy, C₁-C₅ alkanoylamino, C₁-C₅ alkoxycarbonylamino, C₁-C₅ alkylsulfonylamino, aminosulfonyl, C₁-C₅ alkylaminosulfonyl, C₁-C₅ dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, oxo, trifluoromethyl, trifluoromethoxy, nitro; or amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C₁-C₅ alkyl; or ureido wherein either nitrogen atom is optionally independently substituted with C₁-C₅ alkyl; or C₁-C₅ alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone; R⁸ is C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, carbocycle, heterocyclyl, aryl, heteroaryl, carbocycle-C₁-C₈ alkyl, aryl-C₁-C₈ alkyl, aryl-C₁-C₈ haloalkyl, heterocyclyl-C₁-C₈ alkyl, heteroaryl-C₁-C₈ alkyl, carbocycle-C₂-C₈ alkenyl, aryl-C₂-C₈ alkenyl, heterocyclyl-C₂-C₈ alkenyl, or heteroaryl-C₂-C₈ alkenyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁸ is independently C₁-C₅ alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈ cycloalkyl, phenyl, C₁-C₅ alkoxy, phenoxy, C₁-C₅ alkanoyl, aroyl, C₁-C₅ alkoxycarbonyl, C₁-C₅ alkanoyloxy, aminocarbonyloxy, C₁-C₅ alkylaminocarbonyloxy, C₁-C₅ dialkylaminocarbonyloxy, aminocarbonyl, C₁-C₅ alkylaminocarbonyl, C₁-C₅ dialkylaminocarbonyl, C₁-C₅ alkanoylamino, C₁-C₅ alkoxycarbonylamino, C₁-C₅ alkylsulfonylamino, aminosulfonyl, C₁-C₅ alkylaminosulfonyl, C₁-C₅ dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, oxo, trifluoromethyl, nitro; or amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C₁-C₅ alkyl; or ureido wherein either nitrogen atom is optionally independently substituted with C₁-C₅ alkyl; or C₁-C₅ alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone; wherein R⁸ cannot be trifluoromethyl; or a tautomer, prodrug, solvate, or salt thereof.
 25. A compound of Formula (IB) according to claim 24, wherein: R¹ is phenyl, naphthyl, indanyl, indenyl, dihydrobenzofuranyl, benzofuranyl, chromanyl, dihydroindolyl, indolyl, dihydrobenzothienyl, benzothienyl, benzodioxolanyl, dihydrobenzoxazolyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzimidazolyl, dihydroquinolinyl, quinolinyl, dihydroisoquinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, furanyl, thienyl, pyrrolyl, pyridinyl, pyrazinyl, or pyrimidinyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R¹ is independently C₁-C₃ alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, C₂-C₃ alkenyloxy, C₁-C₃ alkanoyl, C₁-C₃ alkoxycarbonyl, C₁-C₃ alkanoyloxy, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, or C₁-C₃ alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone; wherein each substituent group of R¹ is optionally independently substituted with a substituent group selected from methyl, methoxy, halogen, hydroxy, oxo, cyano, or amino; R² and R³ are each independently hydrogen or C₁-C₃ alkyl, or R² and R³ together with the carbon atom they are commonly attached to form a C₃-C₆ spiro cycloalkyl ring; R⁴ is C₁-C₃ alkyl or C₂-C₃ alkenyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁴ is independently methyl, hydroxy, fluoro, chloro, bromo, or oxo; R⁵ is an imidazolyl, pyridinyl, indolyl, azaindolyl, diazaindolyl, benzofuranyl, furanopyridinyl, furanopyrimidinyl, benzothienyl, thienopyridinyl, thienopyrimidinyl, benzoxazolyl, oxazolopyridinyl, benzothiazolyl, thiazolopyridinyl, benzimidazolyl, imidazolopyridinyl, quinolinyl, or isoquinolinyl group, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁵ is independently C₁-C₃ alkyl, C₂-C₃ alkenyl, phenyl, C₁-C₃ alkoxy, methoxycarbonyl, aminocarbonyl, C₁-C₃ alkylaminocarbonyl, C₁-C₃ dialkylaminocarbonyl, beterocyclylcarbonyl, hydroxy, fluoro, chloro, bromo, cyano, trifluoromethyl, or C₁-C₃ alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of R⁵ is optionally independently substituted with a substituent group selected from methyl, methoxy, hydroxy, fluoro, chloro, bromo, oxo or trifluoromethyl, R⁶ and R⁷ are each independently hydrogen, C₁₋₅ alkyl, C₁₋₅ alkoxy, C₂₋₅ alkenyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, phenethyl, phenoxy, hydroxy or C₁-C₅ alkylthio wherein the sulfur atom is oxidized to a sulfoxide or sulfone, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁶ and R⁷ are independently methyl, methoxy, halogen, hydroxy, cyano, oxo or trifluoromethyl; R⁸ is C₁₋₅ alkyl, C₂₋₅ alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl, cyclopentylethyl, cyclohexylethyl, phenethyl, or phenyl-difluoromethyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁸ is independently methyl, methoxy, hydroxy, halogen, cyano, or trifluoromethyl; wherein R⁸ cannot be trifluoromethyl; or a tautomer, prodrug, solvate, or salt thereof.
 26. A compound of Formula (IB) according to claim 24, wherein: R¹ is phenyl, thienyl, naphthyl, chromanyl, pyridinyl, dihydrobenzofuranyl, or benzofuranyl, each optionally independently substituted with one or two substituent groups, wherein each substituent group of R¹ is independently methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, fluoro, chloro, bromo, hydroxy, oxo or cyano; R² and R³ are each independently C₁-C₃ alkyl, or R² and R³ together with the carbon atom they are commonly attached to form a spiro cyclopropyl or cyclobutyl ring; R⁴ is C₁-C₃ alkyl; R⁵ is a pyridinyl, indolyl, azaindolyl, benzofuranyl, furanopyridinyl, benzothienyl, thienopyridinyl, benzoxazolyl, benzimidazolyl, quinolinyl, or isoquinolinyl group, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁵ is independently methyl, phenyl, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, morpholinylcarbonyl, methoxy, hydroxy, fluoro, chloro, bromo, cyano, or trifluoromethyl, R⁶ and R⁷ are each independently hydrogen, C₁₋₅ alkyl, benzyl, hydroxy or C₁-C₅ alkylthio wherein the sulfur atom is oxidized to a sulfoxide or sulfone, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁶ and R⁷ are independently methyl, or oxo; and R⁸ is C₁₋₅ alkyl, cyclopropyl, cyclopentylmethyl, cyclohexylmethyl or benzyl, or a tautomer, prodrug, solvate, or salt thereof.
 27. A compound of Formula (IB) according to claim 24, wherein: R¹ is phenyl, dihydrobenzofuranyl, benzofuranyl or pyridinyl substituted with one or two substituent groups, wherein each substituent group of R¹ is independently methyl, methoxy, fluoro, chloro, bromo, trifuoromethyl, trifluoromethoxy, cyano or hydroxy; R² and R³ are each independently C₁-C₃ alkyl; R⁴ is CH₂; R⁵ is a pyridinyl, indolyl, azaindolyl, benzimidazolyl, quinolinyl, or isoquinolinyl group, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁵ is independently methyl, fluoro, chloro, cyano or trifluoromethyl, R⁶ and R⁷ are each independently hydrogen, methyl, ethyl, propyl, butyl, isobutyl, acetyl, formyl, methylsulfonyl or hydroxy, and R⁸ is methyl, ethyl, n-propyl, i-propyl, cyclopropyl, cyclopentylmethyl or cyclohexylmethyl; or a tautomer, prodrug, solvate, or salt thereof.
 28. A compound of Formula (IB) according to claim 24, wherein: R¹ is phenyl substituted with a methoxy group and a fluoro, or is a phenyl substituted with a hydroxy group and a fluoro; R² and R³ are each independently methyl; R⁴ is CH₂; R⁵ is a quinolinyl, azaindolyl, pyridinyl or indolyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁵ is independently methyl, fluoro, chloro, trifluoromethyl or cyano; R⁶ and R⁷ are each independently hydrogen, methyl or isobutyl; and R⁸ is methyl, cyclopropyl, or cyclohexylmethyl; or a tautomer, prodrug, solvate, or salt thereof.
 29. A compound of Formula (IB) according to claim 24, wherein: R¹ is an aryl or heteroaryl group, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R¹ is independently C₁-C₅ alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈ cycloalkyl, aryl, C₁-C₅ alkoxy, C₂-C₅ alkenyloxy, C₂-C₅ alkynyloxy, aryloxy, acyl, C₁-C₅ alkoxycarbonyl, C₁-C₅ alkanoyloxy, aminocarbonyl, C₁-C₅ alkylaminocarbonyl, di-C₁-C₅alkylaminocarbonyl, aminocarbonyloxy, C₁-C₅ alkylaminocarbonyloxy, di-C₁-C₅alkylaminocarbonyloxy, C₁-C₅ alkanoylamino, C₁-C₅ alkoxycarbonylamino, C₁-C₅ alkylsulfonylamino, C₁-C₅ alkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, nitro, or amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C₁-C₅ alkyl or aryl; or ureido wherein either nitrogen atom is optionally independently substituted with C₁-C₅ alkyl; or C₁-C₅ alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone; wherein each substituent group of R¹ is independently optionally substituted with one to three substituent groups selected from C₁-C₃alkyl, C-C₃alkoxy, halogen, hydroxy, oxo, cyano or amino. R² and R³ are each independently hydrogen or C₁-C₅ alkyl, or R² and R³ together with the carbon atom they are commonly attached to form a C₃-C₈ spiro cycloalkyl ring; R⁴ is C₁-C₅ alkyl, C₂-C₅ alkenyl, or C₂-C₅ alkynyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁴ is independently C₁-C₃ alkyl, hydroxy, halogen, or oxo; R⁵ is a heteroaryl group optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁵ is independently C₁-C₅ alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈ cycloalkyl, heterocyclyl, aryl, heteroaryl, C₁-C₅ alkoxy, C₂-C₅ alkenyloxy, C₂-C₅ alkynyloxy, aryloxy, acyl, C₁-C₅ alkoxycarbonyl, C₁-C₅ alkanoyloxy, aminocarbonyl, C₁-C₅ alkylaminocarbonyl, di-C₁-C₅alkyl-aminocarbonyl, aminocarbonyloxy, C₁-C₅ alkylaminocarbonyloxy, di-C₁-C₅ alkyl-aminocarbonyloxy, C₁-C₅ alkanoylamino, C₁-C₅ alkoxycarbonylamino, C₁-C₅ alkylsulfonylamino, C₁-C₅ alkylaminosulfonyl, di-C₁-C₅ alkyl-aminosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, or amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C₁-C₅ alkyl; or ureido wherein either nitrogen atom is optionally independently substituted with C₁-C₅ alkyl; or C₁-C₅ alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of R⁵ is optionally independently substituted with one to three substituent groups selected from C₁-C₃ alkyl, C₁-C₃ alkoxy, halogen, hydroxy, oxo, cyano, amino, or trifluoromethyl; R⁶ and R⁷ are each hydrogen; and R⁸ is C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, carbocycle, heterocyclyl, aryl, heteroaryl, carbocycle-C₁-C₈ alkyl, aryl-C₁-C₈ alkyl, aryl-C₁-C₈ haloalkyl, heterocyclyl-C₁-C₈ alkyl, heteroaryl-C₁-C₈ alkyl, carbocycle-C₂-C₈ alkenyl, aryl-C₂-C₈ alkenyl, heterocyclyl-C₂-C₈ alkenyl, or heteroaryl-C₂-C₈ alkenyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁸ is independently C₁-C₅ alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, C₃-C₈ cycloalkyl, phenyl, C₁-C₅ alkoxy, phenoxy, C₁-C₅ alkanoyl, aroyl, C₁-C₅ alkoxycarbonyl, C₁-C₅alkanoyloxy, aminocarbonyl, C₁-C₅alkylaminocarbonyl, di-C₁-C₅alkylaminocarbonyl, aminocarbonyloxy, C₁-C₅alkylaminocarbonyloxy, di-C₁-C₅alkylaminocarbonyloxy, C₁-C₅ alkanoylamino, C₁-C₅ alkoxycarbonylamino, C₁-C₅ alkylsulfonylamino, C₁-C₅ alkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, or nitro; or amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C₁-C₅ alkyl; or ureido wherein either nitrogen atom is optionally independently substituted with C₁-C₅ alkyl; or C₁-C₅ alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone; wherein R⁸ cannot be trifluoromethyl; or a tautomer, prodrug, solvate, or salt thereof.
 30. A compound of Formula (IB) according to claim 24, wherein: R¹ is phenyl, naphthyl, indanyl, indenyl, dihydrobenzofuranyl, dihydroindolyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, thienyl, furanyl, pyrrolyl, pyridinyl, pyrazinyl, pyrimidinyl, indolyl, benzofuranyl or benzothienyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R¹ is independently C₁-C₃ alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl, C₁-C₃ alkoxy, C₂-C₃ alkenyloxy, C₂-C₃ alkynyloxy, C₁-C₃ alkanoyl, C₁-C₃ alkoxycarbonyl, C₁-C₃ alkanoyloxy, halogen, hydroxy, carboxy, cyano, trifluoromethyl, nitro, or C₁-C₃ alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone; R² and R³ are each independently hydrogen or C₁-C₃ alkyl, or R² and R³ together with the carbon atom they are commonly attached to form a C₃-C₆ spiro cycloalkyl ring; R⁴ is C₁-C₃ alkyl or C₂-C₃ alkenyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁴ is independently methyl, hydroxy, fluoro, chloro, bromo, or oxo; R⁵ is a pyridyl, indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, quinolinyl, or isoquinolinyl group, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁵ is independently C₁-C₃ alkyl, C₂-C₃ alkenyl, phenyl, C₁-C₃ alkoxy, fluoro, chloro, bromo, cyano, trifluoromethyl, or C₁-C₃ alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of R⁵ is optionally independently substituted with a substituent group selected from methyl, methoxy, fluoro, chloro, bromo, or trifluoromethyl; R⁶ and R⁷ are each hydrogen; and R⁸ is C₁₋₅ alkyl, C₂₋₅ alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, benzyl, cyclopentylethyl, cyclohexylethyl, phenethyl, or phenyl-difluoromethyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁸ is independently methyl, methoxy, hydroxy, halogen, cyano, or trifluoromethyl; wherein R⁸ cannot be trifluoromethyl; or a tautomer, prodrug, solvate, or salt thereof.
 31. A compound of Formula (IB) according to claim 24, wherein: R¹ is phenyl, pyridinyl, dihydrobenzofuranyl, or benzofuranyl, each optionally independently substituted with one or two substituent groups, wherein each substituent group of R¹ is independently methyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, hydroxy, or cyano; R² and R³ are each independently C₁-C₃ alkyl, or R² and R³ together with the carbon atom they are commonly attached to form a spiro cyclopropyl or cyclobutyl ring; R⁴ is C₁-C₃ alkyl; R⁵ is a pyridyl, indolyl, benzofuranyl, benzoxazolyl, benzimidazolyl, quinolinyl, or isoquinolinyl group, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁵ is independently methyl, phenyl, fluoro, chloro, cyano, or trifluoromethyl; R⁶ and R⁷ are each hydrogen; and R⁸ is C₁₋₅ alkyl, cyclopropyl, cyclopentylmethyl, cyclohexylmethyl or benzyl, or a tautomer, prodrug, solvate, or salt thereof.
 32. A compound of Formula (IB) according to claim 24, wherein: R¹ is phenyl substituted with one or two substituent groups, wherein each substituent group of R¹ is independently methoxy, fluoro, chloro, bromo or hydroxy; R² and R³ are each independently C₁-C₃ alkyl; R⁴ is CH₂; R⁵ is a pyridyl, indolyl, benzimidazolyl, quinolinyl, or isoquinolinyl group, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁵ is independently methyl, fluoro, chloro, or trifluoromethyl; R⁶ and R⁷ are each hydrogen; and R⁸ is methyl, ethyl, n-propyl, i-propyl, cyclopentylmethyl or cyclohexylmethyl; or a tautomer, prodrug, solvate, or salt thereof.
 33. A compound of Formula (IB) according to claim 24, wherein: R¹ is phenyl substituted with a methoxy group and a fluoro, or is a phenyl substituted with a hydroxy group and a fluoro; R² and R³ are each independently methyl; R⁴ is CH₂; R⁵ is a pyridyl or indolyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R⁵ is independently methyl, fluoro or chloro; R⁶ and R⁷ are each hydrogen; and R⁸ is methyl or cyclohexylmethyl; or a tautomer, prodrug, solvate, or salt thereof.
 34. A compound according to claim 24 selected from: 1-(2,6-Dichloro-pyridin-4-ylmethyl)-3-(5-fluoro-2-methoxy-phenyl)-1,3-dimethyl-butylamine; 1-Ethyl-3-(5-fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-butylamine; 1-Cyclohexylmethyl-3-(5-fluoro-2-methoxy-phenyl)-1-(1H-indol-2-ylmethyl)-3-methyl-butylamine; 1-(2-Chloro-quinolin-4-ylmethyl)-1-cyclopentyl-3-(5-fluoro-2-methoxy-phenyl)-3-methyl-butylamine; 1-(2-Chloro-pyridin-4-ylmethyl)-1-cyclopentylmethyl-3-(5-fluoro-2-methoxy-phenyl)-3-methyl-butylamine; 3-(5-Fluoro-2-methoxy-phenyl)-1,3-dimethyl-1-quinolin-4-ylmethyl-butylamine; 1-Cyclopropyl-3-(5-fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-butylamine; 3-(5-Fluoro-2-methoxy-phenyl)-1,3-dimethyl-1-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-butylamine; 1-Cyclopropyl-3-(5-fluoro-2-methoxy-phenyl)-3-methyl-1-(1H-pyrrolo[2,3-c]pyridin-2-ylmethyl)-butylamine; 2-[3-Amino-1,1,3-trimethyl-4-(1H-pyrrolo[2,3-c]pyridin-2-yl)-butyl]-4-fluoro-phenol; 2-[2-Amino-4-(5-fluoro-2-methoxy-phenyl)-2,4-dimethyl-pentyl]-4-methyl-1H-indole-6-carbonitrile; or a tautomer, prodrug, solvate, or salt thereof.
 35. A compound according to claim 24 selected from: 1-(2,6-Dichloro-pyridin-4-ylmethyl)-3-(5-fluoro-2-methoxy-phenyl)-1,3-dimethyl-butylamine; 1-Ethyl-3-(5-fluoro-2-methoxy-phenyl)-3-methyl-1-quinolin-4-ylmethyl-butylamine; 1-Cyclohexylmethyl-3-(5-fluoro-2-methoxy-phenyl)-1-(1H-indol-2-ylmethyl)-3-methyl-butylamine; 1-(2-Chloro-quinolin-4-ylmethyl)-1-cyclopentyl-3-(5-fluoro-2-methoxy-phenyl)-3-methyl-butylamine; 1-(2-Chloro-pyridin-4-ylmethyl)-1-cyclopentylmethyl-3-(5-fluoro-2-methoxy-phenyl)-3-methyl-butylamine; or a tautomer, prodrug, solvate, or salt thereof.
 36. A pharmaceutical composition comprising an effective amount of a compound according to claim 24, or a tautomer, prodrug, solvate, or salt thereof, and a pharmaceutically acceptable excipient or carrier.
 37. A method of modulating the glucocorticoid receptor function in a patient, the method comprising administering to the patient an effective amount of a pharmaceutically acceptable compound according to claim 24, or a tautomer, prodrug, solvate, or salt thereof.
 38. A method of treating a disease-state or condition mediated by the glucocorticoid receptor function in a patient in need of such treatment, the method comprising administering to the patient an effective amount of a pharmaceutically acceptable compound according to claim 24, or a tautomer, prodrug, solvate, or salt thereof.
 39. A method of treating a disease-state or condition selected from: type II diabetes, obesity, cardiovascular diseases, hypertension, arteriosclerosis, neurological diseases, adrenal and pituitary tumors, and glaucoma, in a patient in need of such treatment, the method comprising administering to the patient an effective amount of a pharmaceutically acceptable compound according to claim 24, or a tautomer, prodrug, solvate, or salt thereof.
 40. A method of treating a disease characterized by inflammatory, allergic, or proliferative processes, in a patient in need of such treatment, the method comprising administering to the patient an effective amount of a pharmaceutically acceptable compound according to claim 24, or a tautomer, prodrug, solvate, or salt thereof.
 41. The method according to claim 40, wherein the disease is selected from: (i) lung diseases; (ii) rheumatic diseases or autoimmune diseases or joint diseases; (iii) allergic diseases; (iv) vasculitis diseases; (v) dermatological diseases; (vi) renal diseases; (vii) hepatic diseases; (viii) gastrointestinal diseases; (ix) proctological diseases; (x) eye diseases; (xi) diseases of the ear, nose, and throat (ENT) area; (xii) neurological diseases; (xiii) blood diseases; (xiv) tumor diseases; (xv) endocrine diseases; (xvi) organ and tissue transplantations and graft-versus-host diseases; (xvii) severe states of shock; (xviii) substitution therapy; and (xix) pain of inflammatory genesis.
 42. The method according to claim 40, wherein the disease is selected from: type I diabetes, osteoarthritis, Guillain-Barre syndrome, restenosis following percutaneous transluminal coronary angioplasty, Alzheimer disease, acute and chronic pain, atherosclerosis, reperfusion injury, bone resorption diseases, congestive heart failure, myocardial infarction, thermal injury, multiple organ injury secondary to trauma, acute purulent meningitis, necrotizing enterocolitis, and syndromes associated with hemodialysis, leukopheresis, and granulocyte transfusion.
 43. A method of treating a disease-state or condition mediated by the glucocorticoid receptor function in a patient in need of such treatment, the method comprising sequentially or simultaneously administering to the patient: (a) an effective amount of a pharmaceutically acceptable compound according to claim 24, or a tautomer, prodrug, solvate, or salt thereof; and (b) a pharmaceutically acceptable glucocorticoid.
 44. A kit for the in vitro diagnostic determination of the glucocorticoid receptor function in a sample, comprising: (a) a diagnostically effective amount of a compound according to claim 24or a tautomer, prodrug, solvate, or salt thereof; and (b) instructions for use of the diagnostic kit.
 45. A method of making a compound of Formula (IB) according to claim 24 wherein R⁶ and R⁷ are both hydrogen:

where R¹ is an optionally substituted 2-alkoxyphenyl group and R², R³, R⁴, R⁵, and R⁸ are as defined in claim 24, the method comprising: reacting a compound of Formula (XIX) wherein each R is alkyl with a suitable organometallic reagent R⁵R⁴M where M is Li or MgX and X is Cl, Br, or I, in a suitable solvent to form the compound of Formula (IB)


46. A method of making a compound of Formula (IB) according to claim 24 wherein R⁶ and R⁷ are both hydrogen:

where R¹ is an optionally substituted 2-alkoxyphenyl group and R², R³, R⁴, R⁵, and R⁸ are as defined in claim 24, the method comprising: (a) reacting an optionally substituted phenol of Formula (XIV) with an acryloyl chloride of Formula (XV) in the presence of a suitable base, followed by cyclization of the intermediate ester by treatment with a suitable Lewis acid to form a lactone of Formula (XVI)

(b) reacting the lactone of Formula (XVI) with a suitable amine HNR″R′″, followed by treatment of the intermediate phenol with an alkyl halide RX, where R is alkyl and X is halogen, in the presence of a suitable base to form an amide of Formula (XVII)

(c) reacting the amide of Formula (XVII) with a suitable organometallic reagent R⁸M, where M is Li or MgX and X is Cl, Br, or I, in a suitable solvent to form a ketone of Formula (XVIII)

(d) reacting the compound of Formula (XVIII) with an alkylsulfinamide RS(O)NH₂ wherein R is alkyl, and a suitable Lewis acid to produce the compound of Formula (XIX)

(e) reacting a compound of Formula (XIX) wherein each R is alkyl with a suitable organometallic reagent R⁵R⁴M where M is Li or MgX and X is Cl, Br, or I, in a suitable solvent to form the compound of Formula (IB)


47. A method of making a compound of Formula (IB) according to claim 24 wherein R⁶ and R⁷ are both hydrogen:

where R¹, R², R³, R⁴, R⁵ and R⁸ are as defined in claim 24, the method comprising: reacting a compound of Formula (XXIV) with an organometallic reagent R⁵R⁴M where M is Li or MgX and X is Cl, Br, or I, in a suitable solvent to form the compound of Formula (IB):

where R is alkyl and R¹, R², R³, R⁴, R⁵ and R⁸ are as defined in claim
 24. 48. A method of making a compound of Formula (IB) according to claim 24 wherein R⁶ and R⁷ are both hydrogen:

where R¹, R², R³, R⁴, R⁵ and R⁸ are as defined in claim 24, the method comprising: (a′) reacting an amide of Formula (XXI) with a vinyl magnesium bromide bearing R² and R³ of the formula R²R³CH═CHMgBr in a suitable solvent to provide an enone of Formula (XXII)

(b′) reacting the enone of Formula (XXII) with a suitable organocopper reagent generated from an organometallic reagent R¹M, where M is Li or MgX, and a copper salt CuX, where X is Cl, Br or I, in a suitable solvent to form a ketone of Formula (XXIII)

(c′) reacting the compound of Formula (XXIII) with a suitable Lewis acid and an alkylsulfinamide of formula RS(O)NH₂ where R is alkyl to form the compound of Formula (XXIV)

(d′) reacting a compound of Formula (XXIV) with an organometallic reagent R⁵R⁴M where M is Li or MgX and X is Cl, Br, or I, in a suitable solvent to form the compound of Formula (IB):

where R is alkyl and R¹, R², R³, R⁴, R⁵ and R⁸ are as defined in claim
 24. 